Biochemistry, Genetics and Molecular Biology › Molecular Biology

Angiogenesis and VEGF in Cancer

Works Count: 60783

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Description

This cluster of papers focuses on the molecular mechanisms of angiogenesis, including the role of VEGF, endothelial progenitor cells, pericytes, and anti-angiogenic therapy in regulating tumor vasculature and vascular function. It explores the signaling pathways, therapeutic targets, and clinical applications related to angiogenesis.

Keywords

VEGF; endothelial progenitor cells; tumor angiogenesis; anti-angiogenic therapy; vascular endothelial growth factor; pericytes; vascular normalization; endothelial cell behavior; tumor vasculature; angiogenic signaling

Mechanisms of angiogenesis and arteriogenesis

2000-04-01

Peter Carmeliet

Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer

2004-05-01

Napoleone Ferrara , Kenneth J. Hillan , Hans‐Peter Gerber +1 more

Angiogenesis in cancer and other diseases

2000-09-01

Peter Carmeliet , Rakesh K. Jain

Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization

1999-04-01

Tomono Takahashi , Christoph Kalka , Haruchika Masuda +6 more

Mechanisms of angiogenesis

1997-04-01

Werner Risau

Vascular-specific growth factors and blood vessel formation

2000-09-01

George D. Yancopoulos , Samuel Davis , Nicholas W. Gale +3 more

Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo

1993-04-01

K. Jin Kim , Bing Li , Jane Winer +4 more

Tumor Angiogenesis: Therapeutic Implications

1971-11-18

Louis M. Sherwood , Edith E. Parris , Judah Folkman

THE growth of solid neoplasms is always accompanied by neovascularization. This new capillary growth is even more vigorous and continuous than a similar outgrowth of capillary sprouts observed in fresh … THE growth of solid neoplasms is always accompanied by neovascularization. This new capillary growth is even more vigorous and continuous than a similar outgrowth of capillary sprouts observed in fresh wounds or in inflammation.1 Many workers have described the association between growing solid malignant tumors and new vessel growth.2 3 4 5 6 However, it has not been appreciated until the past few years that the population of tumor cells and the population of capillary endothelial cells within a neoplasm may constitute a highly integrated ecosystem. In this ecosystem the mitotic index of the two cell populations may depend upon each other. Tumor cells . . .

Vascular Endothelial Growth Factor Is a Secreted Angiogenic Mitogen

1989-12-08

David W. M. Leung , George Cachianes , Wun-Jing Kuang +2 more

Vascular endothelial growth factor (VEGF) was purified from media conditioned by bovine pituitary folliculostellate cells (FC). VEGF is a heparin-binding growth factor specific for vascular endothelial cells that is able … Vascular endothelial growth factor (VEGF) was purified from media conditioned by bovine pituitary folliculostellate cells (FC). VEGF is a heparin-binding growth factor specific for vascular endothelial cells that is able to induce angiogenesis in vivo. Complementary DNA clones for bovine and human VEGF were isolated from cDNA libraries prepared from FC and HL60 leukemia cells, respectively. These cDNAs encode hydrophilic proteins with sequences related to those of the A and B chains of platelet-derived growth factor. DNA sequencing suggests the existence of several molecular species of VEGF. VEGFs are secreted proteins, in contrast to other endothelial cell mitogens such as acidic or basic fibroblast growth factors and platelet-derived endothelial cell growth factor. Human 293 cells transfected with an expression vector containing a bovine or human VEGF cDNA insert secrete an endothelial cell mitogen that behaves like native VEGF.

Thalidomide is an inhibitor of angiogenesis.

1994-04-26

Robert J. D’Amato , Michael Loughnan , Evelyn Flynn +1 more

Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of angiogenesis induced by basic fibroblast growth factor … Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of angiogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antiangiogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally administered drug for the treatment of many diverse diseases dependent on angiogenesis.

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The Biology of Vascular Endothelial Growth Factor

1997-02-01

Napoleone Ferrara , Terri Davis-Smyth

The establishment of a vascular supply is required for organ development and differentiation as well as for tissue repair and reproductive functions in the adult1. Neovascularization (angiogenesis) is also implicated … The establishment of a vascular supply is required for organ development and differentiation as well as for tissue repair and reproductive functions in the adult1. Neovascularization (angiogenesis) is also implicated in the pathogenesis of a number of disorders. These include: proliferative retinopathies, age-related macular degeneration, tumors, rheumatoid arthritis, and psoriasis1,2. A strong correlation has been noted between density of microvessels in primary breast cancers and their nodal metastases and patient survival3. Similarly, a correlation has been reported between vascularity and invasive behavior in several other tumors4–6.

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Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis

1996-08-01

Douglas Hanahan , Judah Folkman

Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment

1998-04-14

Susan K. Hobbs , Wayne L. Monsky , Fan Yuan +4 more

Novel anti-neoplastic agents such as gene targeting vectors and encapsulated carriers are quite large (approximately 100–300 nm in diameter). An understanding of the functional size and physiological regulation of transvascular … Novel anti-neoplastic agents such as gene targeting vectors and encapsulated carriers are quite large (approximately 100–300 nm in diameter). An understanding of the functional size and physiological regulation of transvascular pathways is necessary to optimize delivery of these agents. Here we analyze the functional limits of transvascular transport and its modulation by the microenvironment. One human and five murine tumors including mammary and colorectal carcinomas, hepatoma, glioma, and sarcoma were implanted in the dorsal skin-fold chamber or cranial window, and the pore cutoff size, a functional measure of transvascular gap size, was determined. The microenvironment was modulated: ( i ) spatially, by growing tumors in subcutaneous or cranial locations and ( ii ) temporally, by inducing vascular regression in hormone-dependent tumors. Tumors grown subcutaneously exhibited a characteristic pore cutoff size ranging from 200 nm to 1.2 μm. This pore cutoff size was reduced in tumors grown in the cranium or in regressing tumors after hormone withdrawal. Vessels induced in basic fibroblast growth factor-containing gels had a pore cutoff size of 200 nm. Albumin permeability was independent of pore cutoff size. These results have three major implications for the delivery of therapeutic agents: ( i ) delivery may be less efficient in cranial tumors than in subcutaneous tumors, ( ii ) delivery may be reduced during tumor regression induced by hormonal ablation, and ( iii ) permeability to a molecule is independent of pore cutoff size as long as the diameter of the molecule is much less than the pore diameter.

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Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium

1995-07-01

Guo‐Hua Fong , Janet Rossant , Marina Gertsenstein +1 more

Molecular mechanisms and clinical applications of angiogenesis

2011-05-01

Peter Carmeliet , Rakesh K. Jain

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Angiogenesis in health and disease

2003-05-30

Peter Carmeliet

Angiogenesis in cancer, vascular, rheumatoid and other disease

1995-01-01

Judah Folkman

The biology of VEGF and its receptors

2003-05-30

Napoleone Ferrara , Hans‐Peter Gerber , Jennifer LeCouter

Modes of resistance to anti-angiogenic therapy

2008-07-24

Gabriele Bergers , Douglas Hanahan

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Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele

1996-04-01

Peter Carmeliet , Valérie Ferreira , Georg Breier +7 more

Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice

1995-07-01

Fouad Shalaby , Janet Rossant , Terry P. Yamaguchi +4 more

Molecular regulation of vessel maturation

2003-05-30

Rakesh K. Jain

Isolation of Putative Progenitor Endothelial Cells for Angiogenesis

1997-02-14

Takayuki Asahara , Toyoaki Murohara , Alison Sullivan +6 more

Putative endothelial cell (EC) progenitors or angioblasts were isolated from human peripheral blood by magnetic bead selection on the basis of cell surface antigen expression. In vitro, these cells differentiated … Putative endothelial cell (EC) progenitors or angioblasts were isolated from human peripheral blood by magnetic bead selection on the basis of cell surface antigen expression. In vitro, these cells differentiated into ECs. In animal models of ischemia, heterologous, homologous, and autologous EC progenitors incorporated into sites of active angiogenesis. These findings suggest that EC progenitors may be useful for augmenting collateral vessel growth to ischemic tissues (therapeutic angiogenesis) and for delivering anti- or pro-angiogenic agents, respectively, to sites of pathologic or utilitarian angiogenesis.

Requisite Role of Angiopoietin-1, a Ligand for the TIE2 Receptor, during Embryonic Angiogenesis

1996-12-01

Chitra Suri , Pamela F. Jones , Sybill Patan +5 more

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Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a lewis lung carcinoma

1994-10-21

M. OʼReilly

Basic and Therapeutic Aspects of Angiogenesis

2011-09-01

Michael Potente , Holger Gerhardt , Peter Carmeliet

Vascular Endothelial Growth Factor: Basic Science and Clinical Progress

2004-08-01

Napoleone Ferrara

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. Hypoxia has been shown to be a … Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. Hypoxia has been shown to be a major inducer of VEGF gene transcription. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2) are high-affinity VEGF receptors. The role of VEGF in developmental angiogenesis is emphasized by the finding that loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF is critical also for reproductive and bone angiogenesis. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. In situ hybridization studies demonstrate expression of VEGF mRNA in the majority of human tumors. Anti-VEGF monoclonal antibodies and other VEGF inhibitors block the growth of several tumor cell lines in nude mice. Clinical trials with various VEGF inhibitors in a variety of malignancies are ongoing. Very recently, an anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the Food and Drug Administration as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.

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Angiogenesis as a therapeutic target

2005-12-01

Napoleone Ferrara , Robert S. Kerbel

Role of angiogenesis in tumor growth and metastasis

2002-12-16

J Folkman

VEGF receptor signalling ? in control of vascular function

2006-04-21

Anna‐Karin Olsson , Anna Dimberg , Johan Kreuger +1 more

Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene

1996-04-01

Napoleone Ferrara , Karen Carver-Moore , Helen Chen +6 more

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Endothelial Progenitor Cells

2004-08-20

Carmen Urbich , Stefanie Dimmeler

Infusion of different hematopoietic stem cell populations and ex vivo expanded endothelial progenitor cells augments neovascularization of tissue after ischemia and contributes to reendothelialization after endothelial injury, thereby, providing a … Infusion of different hematopoietic stem cell populations and ex vivo expanded endothelial progenitor cells augments neovascularization of tissue after ischemia and contributes to reendothelialization after endothelial injury, thereby, providing a novel therapeutic option. However, controversy exists with respect to the identification and the origin of endothelial progenitor cells. Overall, there is consensus that endothelial progenitor cells can derive from the bone marrow and that CD133/VEGFR2 cells represent a population with endothelial progenitor capacity. However, increasing evidence suggests that there are additional bone marrow-derived cell populations (eg, myeloid cells, “side population” cells, and mesenchymal cells) and non-bone marrow-derived cells, which also can give rise to endothelial cells. The characterization of the different progenitor cell populations and their functional properties are discussed. Mobilization and endothelial progenitor cell-mediated neovascularization is critically regulated. Stimulatory (eg, statins and exercise) or inhibitory factors (risk factors for coronary artery disease) modulate progenitor cell levels and, thereby, affect the vascular repair capacity. Moreover, recruitment and incorporation of endothelial progenitor cells requires a coordinated sequence of multistep adhesive and signaling events including adhesion and migration (eg, by integrins), chemoattraction (eg, by SDF-1/CXCR4), and finally the differentiation to endothelial cells. This review summarizes the mechanisms regulating endothelial progenitor cell-mediated neovascularization and reendothelialization.

VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia

2003-06-16

Holger Gerhardt , Matt Golding , Marcus Fruttiger +7 more

Vascular endothelial growth factor (VEGF-A) is a major regulator of blood vessel formation and function. It controls several processes in endothelial cells, such as proliferation, survival, and migration, but it … Vascular endothelial growth factor (VEGF-A) is a major regulator of blood vessel formation and function. It controls several processes in endothelial cells, such as proliferation, survival, and migration, but it is not known how these are coordinately regulated to result in more complex morphogenetic events, such as tubular sprouting, fusion, and network formation. We show here that VEGF-A controls angiogenic sprouting in the early postnatal retina by guiding filopodial extension from specialized endothelial cells situated at the tips of the vascular sprouts. The tip cells respond to VEGF-A only by guided migration; the proliferative response to VEGF-A occurs in the sprout stalks. These two cellular responses are both mediated by agonistic activity of VEGF-A on VEGF receptor 2. Whereas tip cell migration depends on a gradient of VEGF-A, proliferation is regulated by its concentration. Thus, vessel patterning during retinal angiogenesis depends on the balance between two different qualities of the extracellular VEGF-A distribution, which regulate distinct cellular responses in defined populations of endothelial cells.

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Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease

2004-07-01

Gary K. Owens , Meena S. Kumar , Brian R. Wamhoff

The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms/processes that control differentiation of vascular smooth muscle cells (SMC) during normal … The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms/processes that control differentiation of vascular smooth muscle cells (SMC) during normal development and maturation of the vasculature, as well as how these mechanisms/processes are altered in vascular injury or disease. A major challenge in understanding differentiation of the vascular SMC is that this cell can exhibit a wide range of different phenotypes at different stages of development, and even in adult organisms the cell is not terminally differentiated. Indeed, the SMC is capable of major changes in its phenotype in response to changes in local environmental cues including growth factors/inhibitors, mechanical influences, cell-cell and cell-matrix interactions, and various inflammatory mediators. There has been much progress in recent years to identify mechanisms that control expression of the repertoire of genes that are specific or selective for the vascular SMC and required for its differentiated function. One of the most exciting recent discoveries was the identification of the serum response factor (SRF) coactivator gene myocardin that appears to be required for expression of many SMC differentiation marker genes, and for initial differentiation of SMC during development. However, it is critical to recognize that overall control of SMC differentiation/maturation, and regulation of its responses to changing environmental cues, is extremely complex and involves the cooperative interaction of many factors and signaling pathways that are just beginning to be understood. There is also relatively recent evidence that circulating stem cell populations can give rise to smooth muscle-like cells in association with vascular injury and atherosclerotic lesion development, although the exact role and properties of these cells remain to be clearly elucidated. The goal of this review is to summarize the current state of our knowledge in this area and to attempt to identify some of the key unresolved challenges and questions that require further study.

Circulating Endothelial Progenitor Cells, Vascular Function, and Cardiovascular Risk

2003-02-13

Jonathan Hill , Gloria Zalos , Julian Halcox +4 more

Cardiovascular risk factors contribute to atherogenesis by inducing endothelial-cell injury and dysfunction. We hypothesized that endothelial progenitor cells derived from bone marrow have a role in ongoing endothelial repair and … Cardiovascular risk factors contribute to atherogenesis by inducing endothelial-cell injury and dysfunction. We hypothesized that endothelial progenitor cells derived from bone marrow have a role in ongoing endothelial repair and that impaired mobilization or depletion of these cells contributes to endothelial dysfunction and cardiovascular disease progression.

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Number and Migratory Activity of Circulating Endothelial Progenitor Cells Inversely Correlate With Risk Factors for Coronary Artery Disease

2001-07-06

Mariuca Vasa , Stephan Fichtlscherer , Alexandra Aicher +5 more

Abstract —Recent studies provide increasing evidence that postnatal neovascularization involves bone marrow–derived circulating endothelial progenitor cells (EPCs). The regulation of EPCs in patients with coronary artery disease (CAD) is unclear … Abstract —Recent studies provide increasing evidence that postnatal neovascularization involves bone marrow–derived circulating endothelial progenitor cells (EPCs). The regulation of EPCs in patients with coronary artery disease (CAD) is unclear at present. Therefore, we determined the number and functional activity of EPCs in 45 patients with CAD and 15 healthy volunteers. The numbers of isolated EPCs and circulating CD34/kinase insert domain receptor (KDR)-positive precursor cells were significantly reduced in patients with CAD by ≈40% and 48%, respectively. To determine the influence of atherosclerotic risk factors, a risk factor score including age, sex, hypertension, diabetes, smoking, positive family history of CAD, and LDL cholesterol levels was used. The number of risk factors was significantly correlated with a reduction of EPC levels ( R =−0.394, P =0.002) and CD34-/KDR-positive cells ( R =−0.537, P <0.001). Analysis of the individual risk factors demonstrated that smokers had significantly reduced levels of EPCs ( P <0.001) and CD34-/KDR-positive cells ( P =0.003). Moreover, a positive family history of CAD was associated with reduced CD34-/KDR-positive cells ( P =0.011). Most importantly, EPCs isolated from patients with CAD also revealed an impaired migratory response, which was inversely correlated with the number of risk factors ( R =−0.484, P =0.002). By multivariate analysis, hypertension was identified as a major independent predictor for impaired EPC migration ( P =0.043). The present study demonstrates that patients with CAD revealed reduced levels and functional impairment of EPCs, which correlated with risk factors for CAD. Given the important role of EPCs for neovascularization of ischemic tissue, the decrease of EPC numbers and activity may contribute to impaired vascularization in patients with CAD. The full text of this article is available at http://www.circresaha.org.

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Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth

1997-01-01

Michael S. O’Reilly , Thomas Boehm , Yuen Shing +7 more

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Vascular endothelial growth factor (VEGF) and its receptors

1999-01-01

Gera Neufeld , Tzafra Cohen , Stela Gengrinovitch +1 more

Vascular endothelial growth factor (VEGF) is a highly specific mitogen for vascular endothelial cells. Five VEGF isoforms are generated as a result of alternative splicing from a single VEGF gene. … Vascular endothelial growth factor (VEGF) is a highly specific mitogen for vascular endothelial cells. Five VEGF isoforms are generated as a result of alternative splicing from a single VEGF gene. These isoforms differ in their molecular mass and in biological properties such as their ability to bind to cell-surface heparan-sulfate proteoglycans. The expression of VEGF is potentiated in response to hypoxia, by activated oncogenes, and by a variety of cytokines. VEGF induces endothelial cell proliferation, promotes cell migration, and inhibits apoptosis. In vivo VEGF induces angiogenesis as well as permeabilization of blood vessels, and plays a central role in the regulation of vasculogenesis. Deregulated VEGF expression contributes to the development of solid tumors by promoting tumor angiogenesis and to the etiology of several additional diseases that are characterized by abnormal angiogenesis. Consequently, inhibition of VEGF signaling abrogates the development of a wide variety of tumors. The various VEGF forms bind to two tyrosine-kinase receptors, VEGFR-1 (flt-1) and VEGFR-2 (KDR/flk-1), which are expressed almost exclusively in endothelial cells. Endothelial cells express in addition the neuropilin-1 and neuropilin-2 coreceptors, which bind selectively to the 165 amino acid form of VEGF (VEGF165). This review focuses on recent developments that have widened considerably our understanding of the mechanisms that control VEGF production and VEGF signal transduction and on recent studies that have shed light on the mechanisms by which VEGF regulates angiogenesis.

Angiogenesis in life, disease and medicine

2005-12-01

Peter Carmeliet

Bone Marrow Origin of Endothelial Progenitor Cells Responsible for Postnatal Vasculogenesis in Physiological and Pathological Neovascularization

1999-08-06

Takayuki Asahara , Haruchika Masuda , Tomono Takahashi +6 more

Abstract —Circulating endothelial progenitor cells (EPCs) have been isolated in peripheral blood of adult species. To determine the origin and role of EPCs contributing to postnatal vasculogenesis, transgenic mice constitutively … Abstract —Circulating endothelial progenitor cells (EPCs) have been isolated in peripheral blood of adult species. To determine the origin and role of EPCs contributing to postnatal vasculogenesis, transgenic mice constitutively expressing β-galactosidase under the transcriptional regulation of an endothelial cell–specific promoter (Flk-1/LZ or Tie-2/LZ) were used as transplant donors. Localization of EPCs, indicated by flk-1 or tie-2/lacZ fusion transcripts, were identified in corpus luteal and endometrial neovasculature after inductive ovulation. Mouse syngeneic colon cancer cells (MCA38) were implanted subcutaneously into Flk-1/LZ/BMT (bone marrow transplantation) and Tie-2/LZ/BMT mice; tumor samples harvested at 1 week disclosed abundant flk-1/lacZ and tie-2/lacZ fusion transcripts, and sections stained with X-gal demonstrated that the neovasculature of the developing tumor frequently comprised Flk-1– or Tie-2–expressing EPCs. Cutaneous wounds examined at 4 days and 7 days after skin removal by punch biopsy disclosed EPCs incorporated into foci of neovascularization at high frequency. One week after the onset of hindlimb ischemia, lacZ-positive EPCs were identified incorporated into capillaries among skeletal myocytes. After permanent ligation of the left anterior descending coronary artery, histological samples from sites of myocardial infarction demonstrated incorporation of EPCs into foci of neovascularization at the border of the infarct. These findings indicate that postnatal neovascularization does not rely exclusively on sprouting from preexisting blood vessels (angiogenesis); instead, EPCs circulate from bone marrow to incorporate into and thus contribute to postnatal physiological and pathological neovascularization, which is consistent with postnatal vasculogenesis.

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VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche

2005-12-01

Rosandra N. Kaplan , Rebecca D. Riba , Stergios Zacharoulis +7 more

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Angiopoietin-2, a Natural Antagonist for Tie2 That Disrupts in vivo Angiogenesis

1997-07-04

Peter C. Maisonpierre , Chitra Suri , Pamela F. Jones +7 more

Angiogenesis is thought to depend on a precise balance of positive and negative regulation. Angiopoietin-1 (Ang1) is an angiogenic factor that signals through the endothelial cell–specific Tie2 receptor tyrosine kinase. … Angiogenesis is thought to depend on a precise balance of positive and negative regulation. Angiopoietin-1 (Ang1) is an angiogenic factor that signals through the endothelial cell–specific Tie2 receptor tyrosine kinase. Like vascular endothelial growth factor, Ang1 is essential for normal vascular development in the mouse. An Ang1 relative, termed angiopoietin-2 (Ang2), was identified by homology screening and shown to be a naturally occurring antagonist for Ang1 and Tie2. Transgenic overexpression of Ang2 disrupts blood vessel formation in the mouse embryo. In adult mice and humans, Ang2 is expressed only at sites of vascular remodeling. Natural antagonists for vertebrate receptor tyrosine kinases are atypical; thus, the discovery of a negative regulator acting on Tie2 emphasizes the need for exquisite regulation of this angiogenic receptor system.

What Is the Evidence That Tumors Are Angiogenesis Dependent?

1990-01-03

Judah Folkman

Journal Article What Is the Evidence That Tumors Are Angiogenesis Dependent? Get access Judah Folkman Judah Folkman Search for other works by this author on: Oxford Academic PubMed Google Scholar … Journal Article What Is the Evidence That Tumors Are Angiogenesis Dependent? Get access Judah Folkman Judah Folkman Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 82, Issue 1, 3 January 1990, Pages 4–7, https://doi.org/10.1093/jnci/82.1.4 Published: 03 January 1990 Article history Received: 24 November 1989 Accepted: 27 November 1989 Published: 03 January 1990

Role of the Vascular Endothelial Growth Factor Pathway in Tumor Growth and Angiogenesis

2004-12-08

Daniel J. Hicklin , Lee M. Ellis

New blood vessel formation (angiogenesis) is a fundamental event in the process of tumor growth and metastatic dissemination. Hence, the molecular basis of tumor angiogenesis has been of keen interest … New blood vessel formation (angiogenesis) is a fundamental event in the process of tumor growth and metastatic dissemination. Hence, the molecular basis of tumor angiogenesis has been of keen interest in the field of cancer research. The vascular endothelial growth factor (VEGF) pathway is well established as one of the key regulators of this process. The VEGF/VEGF-receptor axis is composed of multiple ligands and receptors with overlapping and distinct ligand-receptor binding specificities, cell-type expression, and function. Activation of the VEGF-receptor pathway triggers a network of signaling processes that promote endothelial cell growth, migration, and survival from pre-existing vasculature. In addition, VEGF mediates vessel permeability, and has been associated with malignant effusions. More recently, an important role for VEGF has emerged in mobilization of endothelial progenitor cells from the bone marrow to distant sites of neovascularization. The well-established role of VEGF in promoting tumor angiogenesis and the pathogenesis of human cancers has led to the rational design and development of agents that selectively target this pathway. Studies with various anti-VEGF/VEGF-receptor therapies have shown that these agents can potently inhibit angiogenesis and tumor growth in preclinical models. Recently, an anti-VEGF antibody (bevacizumab), when used in combination with chemotherapy, was shown to significantly improve survival and response rates in patients with metastatic colorectal cancer and thus, validate VEGF pathway inhibitors as an important new treatment modality in cancer therapy.

Tumor Angiogenesis and Metastasis — Correlation in Invasive Breast Carcinoma

1991-01-03

Noel Weidner , Joseph P. Semple , William R. Welch +1 more

Experimental evidence suggests that the growth of a tumor beyond a certain size requires angiogenesis, which may also permit metastasis. To investigate how tumor angiogenesis correlates with metastases in breast … Experimental evidence suggests that the growth of a tumor beyond a certain size requires angiogenesis, which may also permit metastasis. To investigate how tumor angiogenesis correlates with metastases in breast carcinoma, we counted microvessels (capillaries and venules) and graded the density of microvessels within the initial invasive carcinomas of 49 patients (30 with metastases and 19 without).

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Tumorigenesis and the angiogenic switch

2003-05-30

Gabriele Bergers , Laura E. Benjamin

Biophysical Studies of the Induced Dimerization of Human VEGF Receptor 1 Binding Domain by Divalent Metals Competing with VEGF-A

2016-12-12

Jean‐François Gaucher , Marie Reille‐Seroussi , Nathalie Gagey‐Eilstein +7 more

Angiogenesis is tightly regulated through the binding of vascular endothelial growth factors (VEGFs) to their receptors (VEGFRs). In this context, we showed that human VEGFR1 domain 2 crystallizes in the … Angiogenesis is tightly regulated through the binding of vascular endothelial growth factors (VEGFs) to their receptors (VEGFRs). In this context, we showed that human VEGFR1 domain 2 crystallizes in the presence of Zn2+, Co2+ or Cu2+ as a dimer that forms via metal-ion interactions and interlocked hydrophobic surfaces. SAXS, NMR and size exclusion chromatography analyses confirm the formation of this dimer in solution in the presence of Co2+, Cd2+ or Cu2+. Since the metal-induced dimerization masks the VEGFs binding surface, we investigated the ability of metal ions to displace the VEGF-A binding to hVEGFR1: using a competition assay, we evidenced that the metals displaced the VEGF-A binding to hVEGFR1 extracellular domain binding at micromolar level.

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Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.

1995-05-01

Harold F. Dvorak , Lawrence F. Brown , Michael Detmar +1 more

Angiogenesis.

1992-06-01

Judah Folkman , Yuen Shing

Regulation of Angiogenesis in Health and DiseaseAngiogenesis is a fundamental process by which new blood vessels are formed (1).It is essential in reproduction, development, and wound repair.Under these conditions, angiogenesis … Regulation of Angiogenesis in Health and DiseaseAngiogenesis is a fundamental process by which new blood vessels are formed (1).It is essential in reproduction, development, and wound repair.Under these conditions, angiogenesis is highly regulated, i.e. turned on for brief periods (days) and then completely inhibited.However, many diseases are driven by persistent unregulated angiogenesis.In arthritis, new capillary blood vessels invade the joint and destroy cartilage.In diabetes, new capillaries in the retina invade the vitreous, bleed, and cause blindness (2).Ocular neovascularization is the most common cause of blindness and dominates approximately 20-eye diseases.Tumor growth and metastasis are angiogenesis-dependent (3, 4).A tumor must continuously stimulate the growth of new capillary blood vessels for the tumor itself to grow.Furthermore, the new blood vessels embedded in a tumor provide a gateway for tumor cells to enter the circulation and to metastasize to distant sites, such as liver, lung, or bone.Capillary blood vessels consist of endothelial cells and pericytes.These two cell types carry all of the genetic information to form tubes, branches, and whole capillary networks.Specific angiogenic molecules can initiate this process.Specific inhibitory molecules can stop it.These molecules with opposing functions appear to be continuously acting in concert to maintain a quiescent microvasculature in which endothelial cell turnover is thousands of days.However, the same endothelial cells can undergo rapid proliferation (5-day turnover) during spurts of angiogenesis, for example in wound healing.The proteins which regulate the coagulation system and the family of proteins which regulate the hematopoietic system, including the colony-stimulating factors, interleukins and erythropoietin ( 5 ) , appear to operate by a similar program.The protein interactions of these latter systems, however, are better understood than are the proteins involved in angiogenesis.Angiogenic factors and inhibitors have been discovered only in the past decade, and while their properties can be listed (Table I), the elucidation of their interactions with each other is only beginning to be uncovered.The same can be said of non-vascular cells, such as macrophages and mast cells, which may modulate the angiogenic response. Angiogenic Molecules

Angiogenic Factors

1987-01-23

Judah Folkman , Michael Klagsbrun

Within the past 2 years, several angiogenic factors have been fully purified, their amino acid sequences determined, and their genes cloned. These polypeptides include acidic and basic fibroblast growth factor, … Within the past 2 years, several angiogenic factors have been fully purified, their amino acid sequences determined, and their genes cloned. These polypeptides include acidic and basic fibroblast growth factor, angiogenin, and transforming growth factors α and β. Other less well characterized angiogenesis factors have also been isolated, some of which are lipids. This article traces the discovery of the angiogenic factors and describes their possible significance in understanding growth regulation of the vascular system. When evaluated according to their putative targets, they appear to fall into two groups: (i) those that act directly on vascular endothelial cells to stimulate locomotion or mitosis, and (ii) those that act indirectly by mobilizing host cells (for example, macrophages) to release endothelial growth factors. In addition to their presence in tumors undergoing neovascularization, the same angiogenic peptides are found in many normal tissues where neovascularization is not occurring. This suggests that physiological expression of angiogenic factors is tightly regulated. In addition to the persistent angiogenesis induced by tumors, it now appears that a variety of nonneoplastic diseases, previously thought to be unrelated, can be considered as "angiogenic diseases" because they are dominated by the pathologic growth of capillary blood vessels.

Multicellularity, Culture Duration, and Hydrogel Stiffness Guide Induced Pluripotent Stem Cell-Derived Endothelial Progenitor Cell Contractility

2025-06-24

Toni M. West , Jiwan Han , Gabriel Peery +2 more

Human induced pluripotent stem cells (hiPSCs) offer patient-specific and immune-evasive sources for generating diverse cell types; yet lack of vascularization in hiPSC-derived tissues remains a major limitation for both therapeutic … Human induced pluripotent stem cells (hiPSCs) offer patient-specific and immune-evasive sources for generating diverse cell types; yet lack of vascularization in hiPSC-derived tissues remains a major limitation for both therapeutic applications and disease modeling. Elucidating the mechanisms underlying vascular network formation in hiPSC-derived cells is therefore imperative. We and others have previously demonstrated that hiPSC-derived endothelial progenitor cells (hiPSC-EPs) self-assemble into lumenized microvascular networks when cultured in 3D norbornene-functionalized hyaluronic acid-based hydrogels. Herein we investigated the early period of culturing to characterize contractility of hiPSC-EPs. We hypothesized that multi-cell cooperativity would increase over time and would be dependent on the original hydrogel storage modulus. To quantify cellular contractility either 4 or 7 days after en-capsulation, 3D kinematic analysis was performed on single and small multi-cell clusters of hiPSC-EPs embedded in NorHA-based hydrogels. Contractile responses were significantly and non-linearly influenced by multicellularity, culture duration, and hydrogel stiffness. Novel to this study was the observation that NorHA hydrogels exhibited compressible behaviors, with greater compressibility occurring in NorHA hydrogels with lower stiffness. Hence, the kine-matic analysis was modified to incorporate separate deviatoric and volumetric strain indices. At day 7, multicellularity synergistically increased both strain components. These findings indicated that hiPSC-EP contractility and mechanical interactions with the hydrogel are governed by culture duration, multicellularity, and hydrogel stiffness; providing mechanical insight on hiPSC-EP self-assembly into microvasculature networks, a critical step towards development of functional vascular tissues for regenerative medicine and disease models.

Local Administration of pCMV-VEGF165 Plasmid Encoding VEGF Stimulates Tissue Regeneration after Cold Injury in Rats

2025-06-24

Olesya V. Shcheblykina , Darya A. Kostina , V. V. Arkhipov +6 more | Safety and Risk of Pharmacotherapy

INTRODUCTION. Frostbite is a common cold injury that is associated with high rates of disability and requires long and difficult treatment. A vascular endothelial growth factor (VEGF)-encoding pCMV-VEGF165 plasmid-based gene … INTRODUCTION. Frostbite is a common cold injury that is associated with high rates of disability and requires long and difficult treatment. A vascular endothelial growth factor (VEGF)-encoding pCMV-VEGF165 plasmid-based gene therapy product designed for therapeutic angiogenesis may be a promising tool to promote microcirculation recovery and accelerate lesion healing in local cold injury. This hypothesis needs to be tested in an experimental animal study. AIM. This study aimed to evaluate the efficacy of the pCMV-VEGF165 plasmid gene therapy product for the management of cold injury of a limb in rats. MATERIALS AND METHODS. The study included 42 mature female outbred white laboratory rats. A third to fourth-degree local cold injury was experimentally induced on the dorsal surface of the left hind paw by applying a neodymium magnet frozen in liquid nitrogen. The animals received periwound injections of the test product (super-coiled circular double-stranded plasmid deoxyribonucleic acid at a dose of 60 μg) and placebo (water for injections) on days 2 and 7 after frostbite modelling. The authors evaluated the general condition of the animals, the condition of the damaged paw, the wound area, the healing rate, the body mass, and, after planned euthanasia, the mass of the hind paws. RESULTS. Starting from day 7, the rats treated with the test product showed significantly faster tissue regeneration at the site of cold injury than the control animals. The mean wound surface area reduction in the test animals amounted to 47.36% [25.55; 55.45], whereas that in the control animals was 28.95±18.55% (p<0.05). On day 10, the test group still had a significantly higher tissue regeneration rate than the control group (58.70±15.35% vs 42.01±17.41%, respectively, p<0.05). Later, there was no statistically significant difference in the wound surface healing rates between the groups, which could probably be attributed to the nature of wound healing in the experimental model since rodent wounds heal predominantly by contraction. CONCLUSIONS. The pCMV-VEGF165 plasmid gene therapy product injected in the periwound area at a dose of 60 μg on days 2 and 7 after cold injury simulation in rats reduces damage, accelerates tissue regeneration under the scab, and expedites scarring.

Human Bone‐Derived Endothelial Cells Mediate Bone Regeneration via Distinct Expression of KIT Ligand

2025-06-23

Xiang Li , Hwan Kim , Allen Chilun Luo +7 more | Advanced Science

Effective bone regeneration remains a significant challenge in surgical practice, particularly due to the limitations associated with autologous bone grafting, such as donor site morbidity and limited bone availability. This … Effective bone regeneration remains a significant challenge in surgical practice, particularly due to the limitations associated with autologous bone grafting, such as donor site morbidity and limited bone availability. This study investigated the potential of human bone-derived endothelial cells (b-ECs) in mediating bone regeneration, especially in conjunction with bone marrow-derived mesenchymal stem cells (bm-MSCs). It is demonstrated that b-ECs retain unique osteoinductive properties post-isolation, crucial for promoting bone formation in vivo. Utilizing ectopic and orthotopic xenograft models in immunodeficient mice, these findings revealed that the synergistic interaction of b-ECs and bm-MSCs induced rapid and substantial bone formation, highlighting the therapeutic potential of b-ECs in bone repair strategies. The distinct expression of KIT ligand (KITLG) in b-ECs emerged as a key factor in these processes. KITLG expression by b-ECs facilitated the recruitment of c-Kit+/CD34+ hematopoietic progenitor cells to the osteovascular niche, leading to robust osteogenic differentiation of bm-MSCs, a process regulated by Notch signaling. Moreover, inducing KITLG expression in non-bone-derived endothelial cells conferred similar osteoinductive capabilities. These findings not only enhance the understanding of the intricate interplay between vascular and bone tissues but also open avenues for developing innovative cell-based approaches for bone regeneration therapy.

Evaluation of Anti-VEGFR2 Specific Photoimmunotherapy for Targeted Regression of Neovascularization in an AMD Model

2025-06-23

Hideto Osada , Takashi Nishimura , Makoto Mitsunaga +5 more | Investigative Ophthalmology & Visual Science

This study aimed to evaluate the efficacy of photoimmunotherapy (PIT) targeting VEGFR2 for the treatment of neovascular AMD and to investigate its potential as a novel therapeutic strategy. DC101-IR700, a … This study aimed to evaluate the efficacy of photoimmunotherapy (PIT) targeting VEGFR2 for the treatment of neovascular AMD and to investigate its potential as a novel therapeutic strategy. DC101-IR700, a conjugate of the anti-mouse VEGFR2 monoclonal antibody DC101 and the photosensitizer IR700, was investigated both in vitro and in vivo. VEGFR2 expression in endothelial cells was confirmed via qPCR and immunocytochemistry. Laser-induced choroidal neovascularization (CNV) was established in C57BL/6J mice. Localization of DC101-IR700 within CNV lesions was assessed by immunofluorescence. After PIT was performed using either a 690 nm near-infrared manual laser or a slit lamp laser, CNV volumes were quantified through confocal microscopy. Cell viability post PIT was measured using MTT assay and cell death in CNV lesions was evaluated using TUNEL staining. DC101-IR700 localized specifically to VEGFR2-positive cells in CNV lesions, and PIT induced significant VEGFR2-dependent cytotoxicity in vitro. In vivo, both PIT and directional PIT using slit lamp laser significantly reduced CNV volumes compared with controls. TUNEL staining confirmed VEGFR2-specific cell death in treated CNV lesions. Directional PIT achieved similar efficacy to PIT, demonstrating its potential as a clinically viable alternative. PIT targeting VEGFR2 selectively induced cell death in pathological neovascular tissues, significantly reducing CNV volume in an AMD model. These findings suggest that VEGFR2-specific PIT represents a promising and targeted approach for treating neovascular AMD, offering advantages over conventional anti-VEGF therapies by potentially decreasing treatment frequency and improving efficacy.

Endothelial Progenitor Cells

2025-06-20

Shahd Al Heijani , Mariam Khalil , Salsabil Haque +3 more | Journal of the American Society of Nephrology

Abstract Endothelial progenitor cells (EPCs) constitute a promising focus for research in regenerative medicine. These cells originate from the bone marrow and other circulating hematopoietic cells and regulate tissue regeneration … Abstract Endothelial progenitor cells (EPCs) constitute a promising focus for research in regenerative medicine. These cells originate from the bone marrow and other circulating hematopoietic cells and regulate tissue regeneration and vascular integrity. EPCs mobilization serves for neovascularization and reendothelialization after injury in multiple organ systems, including the renal and cardiovascular systems. Both their number and function may vary in disease states like chronic kidney disease, depending on severity, comorbid conditions, and other factors. Therefore, circulating EPC count and function have been proposed as markers for vascular health, and their mobilization or replenishment may offer a potential therapy. Delivery of EPC has shown success in repairing injured kidneys in animal models of both chronic and acute kidney injury. This approach may be limited by EPC heterogeneity and incomplete characterization that may be addressed by standardization, engineering, or combination with other therapies. This article aims to review the current state and recent advances in our understanding of the role of EPC in homeostasis and conditions that may lead to their dysregulation in kidney diseases.

Angiopoietins: multifaceted mediators in the pathogenesis of joint-related disorders

2025-06-20

Ruifeng Song , Zhenshun Cheng , Zuping Wu +4 more | Histochemistry and Cell Biology

Macrophages-derived NRG-1 promotes angiogenesis after ischemic stroke via the Akt-mTOR pathway

2025-06-19

Jie Chen , Bo Wang , Danyang Fan +4 more | Neural Regeneration Research

Abstract Acute ischemic stroke remains a significant health concern owing to the limited efficacy of current therapeutic options. In recent years, Neuregulin-1 has exhibited promising neuroprotective effects in cerebral ischemia. … Abstract Acute ischemic stroke remains a significant health concern owing to the limited efficacy of current therapeutic options. In recent years, Neuregulin-1 has exhibited promising neuroprotective effects in cerebral ischemia. However, the sources and functions of Neuregulin-1 have not yet been fully understood, which hinders its translation and broad application. Here, we collected paired clot and peripheral blood samples from patients with acute ischemic stroke to determine the sources of Neuregulin-1. In addition, we established an in vivo transient middle cerebral artery occlusion mouse model to investigate the therapeutic effects of Neuregulin-1 and its underlying molecular biological mechanisms. We observed a significant elevation in serum Neuregulin-1 levels among patients with acute ischemic stroke that correlated with severity of neurological impairment and clinical outcome. Using single-cell sequencing, we identified Neuregulin-1-positive macrophages among peripheral blood mononuclear cells that produced Neuregulin-1 post-ischemia. In addition, Neuregulin-1 promoted repair of the infarcted area, alleviating neuronal and myelin damage and improving overall behavioral recovery in mice. We found that Neuregulin-1 may exert these neuroprotective effects by promoting angiogenesis in the infarct area, and that this effect is mediated by Akt/mTOR/VEGF-dependent signaling. Our findings suggest that peripheral macrophages are a source of Neuregulin-1 post-stroke. Neuregulin-1 exerts its neuroprotective effects by promoting angiogenesis via Akt/mTOR/VEGF-dependent signaling, showing promising clinical translation potential.

Antidiabetic sitagliptin influences tissue regeneration by affecting progenitor cells

2025-06-18

Bárbara Torrecillas-Baena , Victoria Pulido-Escribano , José Manuel Quesada‐Gómez +6 more | Biomedicine & Pharmacotherapy

Aberrant angiogenic signaling in HCC: therapeutic targeting and drug resistance

2025-06-18

Hongtao Zhang , Zhaoming Yang , Zhengwu Jiang +4 more | Frontiers in Oncology

Liver cancer ranks as the sixth most prevalent malignancy globally, with Hepatocellular Carcinoma (HCC) constituting the predominant subtype, thereby imposing a significant burden on public health and presenting limited therapeutic … Liver cancer ranks as the sixth most prevalent malignancy globally, with Hepatocellular Carcinoma (HCC) constituting the predominant subtype, thereby imposing a significant burden on public health and presenting limited therapeutic options. Despite ongoing efforts to innovate treatment modalities, anti-angiogenesis therapy continues to be the primary strategy for managing HCC. Angiogenesis is a pivotal process within the tumor microenvironment, characterized by the formation of new blood vessels that provide essential nutrients and oxygen to proliferating tumors, thereby facilitating their growth and potential metastasis. Numerous angiogenic signaling pathways become dysregulated during this process. Targeting these aberrant pathways can yield significant therapeutic benefits for patients and may even reverse drug resistance. However, these signaling pathways frequently demonstrate intricate crosstalk and interconnections. Elucidating these interactions could represent a crucial strategy for advancing the treatment of HCC. This review provides both mechanistic insights into angiogenic network plasticity and translational strategies to overcome therapeutic bottlenecks in HCC management.

Inhibition of Phosphoglycerate Kinase 1 (PGK1) Decreases Neointimal Hyperplasia after Patch Angioplasty

2025-06-17

Peng Sun , Hao Cui , Changwei Ren +4 more | ACS Applied Bio Materials

Neointimal hyperplasia is a known complication following aorta interventions. In this study, our hypothesis was that inhibiting phosphoglycerate kinase 1 (PGK1) could effectively reduce aortic neointimal hyperplasia in a rat … Neointimal hyperplasia is a known complication following aorta interventions. In this study, our hypothesis was that inhibiting phosphoglycerate kinase 1 (PGK1) could effectively reduce aortic neointimal hyperplasia in a rat model of abdominal aortic patch angioplasty. The role of the glycolytic pathway in patch angioplasty was analyzed by next-generation sequencing data, and the core role of PGK1 was found by differential gene analysis. The rats were allocated into two distinct groups: a control group that did not receive any supplementary treatment and a group treated with NG52, an inhibitor of PGK1, which was administered via a PLGA coating. Abdominal aortic patches were surgically implanted in the rats and subsequently harvested on the 14th day postimplantation for further analysis. Immunohistochemical analysis identified the presence of PGK1-positive cells within the neointima of the rat model subjected to abdominal aortic patch angioplasty. Importantly, the use of NG52 PLGA coating significantly decreased neointimal thickness (p < 0.0001). The mechanism of action of NG52 may involve the inhibition of TGFβ1 expression and the activation of the signaling pathway. Consequently, targeting the PGK1 pathway holds promise as a therapeutic strategy to mitigate aortic neointimal hyperplasia.

An endothelial cell competition assay for determinants of the response to targeted anti-angiogenics

2025-06-17

Michael M. Halford , Michael Y. He , Nancy Amin +4 more | Growth Factors

ABSTRACT/SUMMARYAnti-angiogenics, inhibitors of pathological blood vessel growth, are an important class of targeted agent for the treatment of common cancers and ocular conditions. However, efficacy is compromised by the absence … ABSTRACT/SUMMARYAnti-angiogenics, inhibitors of pathological blood vessel growth, are an important class of targeted agent for the treatment of common cancers and ocular conditions. However, efficacy is compromised by the absence of biomarkers to guide patient selection or inform the management of resistance. We describe an assay for modified endothelial cell (EC) responses to the VEGF-A-neutralizing monoclonal antibody bevacizumab as part of a biomarker discovery program. ECs are transduced by lentivector expressing an experimental or non-silencing shRNA, each co-expressed with a different fluorescent protein. A 1:1 mixed cell population is then cultured with bevacizumab or control antibody under VEGF-A-dependent conditions. A normalized ratio of surviving cells, obtained by flow cytometry analysis, reflects EC resistance or sensitization to bevacizumab mediated by the experimental shRNA. With reagents prepared, the protocol takes 10 days and rigorously quantifies the impact of gene perturbation on the EC response to bevacizumab or other targeted anti-angiogenics.

Cancer-associated VEGFR2R1032Q sustains receptor activation also by promoting ligand-independent hetero-dimerization with co-expressed wild-type VEGFR2 and translocation into lipid rafts

2025-06-14

Cosetta Ravelli , Michela Corsini , Roberto Bresciani +5 more | Neoplasia

Assessment of potential clinical approaches for the expression of prolactin receptor (PRL-R) and vascular endothelial growthfactor (VEGF) in various feline mammarygl and tumors

2025-06-13

Sławomir Giziński , Łukasz Zdrojkowski , J Olszewski +6 more | Polish Journal of Veterinary Sciences

Feline mammary gland tumors are a serious health concern, resulting in a significant reduction in the animal's lifespan and a decrease in the overall quality of life. Malignant tumors often … Feline mammary gland tumors are a serious health concern, resulting in a significant reduction in the animal's lifespan and a decrease in the overall quality of life. Malignant tumors often lead to recurrences and metastases. Among endogenous factors that may influence the development or progression of mammary neoplasia, prolactin (PRL) and vascular endothelial growth factor (VEGF) appear to be of crucial importance. This study involved 60 queens with surgically removed mammary gland tumors, which were subsequently stained with hematoxylin and eosin (HE) and immunofluorescence to assess the expression of PRL and VEGF. Variables considered during analyses included the time of ovariohysterectomy, inflammation severity and clinical tumor behavior. The VEGF expression in tumors exhibited an increase in malignant cases, providing evidence of heightened angiogenesis. A lack of differences in the overall expression of PRL receptor was found between tumor types. However, the lower expression of PRL receptor in tumors with increased inflammation may suggest PRL's immunomodulating functions in feline malignant neoplastic tumors. Interestingly, the absence of positive influence of gonadectomy on tumor behavior highlights the need for further research regarding this form of prevention. High expression of PRL receptor and VEGF only in distant metastases may prompt future research on the proangiogenic function of PRL in feline mammary gland tumors.

The role of tumor-associated endothelial cells in malignant progression and immune evasion of liver cancer

2025-06-12

Shiyun Pu , Tianguang Liu , Yuan Gao +2 more | International Immunopharmacology

A novel combination therapy of anti miR-21 and baculoviral TGFβ1 Gene via PLGA-gelatin-genipin nanocomposite hydrogel for arterial plaque stabilization and angiogenesis

2025-06-12

Paromita Islam , Ahmed Abosalha , Sabrina Schaly +7 more | Research Square (Research Square)

<title>Abstract</title> Atherosclerosis is the primary cause of most cases of coronary artery disease, peripheral arterial disease, and many strokes. It is characterized by pathological vascular smooth muscle cell hyperplasia. Current … <title>Abstract</title> Atherosclerosis is the primary cause of most cases of coronary artery disease, peripheral arterial disease, and many strokes. It is characterized by pathological vascular smooth muscle cell hyperplasia. Current treatment regimens are associated with several adverse effects including hepatotoxicity, hemorrhagic complications, and non-selective cellular inhibition. Plaque stabilization and angiogenesis are critical for mitigating adverse cardiovascular outcomes. Stabilized plaques exhibit reduced vulnerability to rupture, thereby lowering the risk of thrombus formation, myocardial infarction, and ischemic stroke. Transforming Growth Factor Beta 1 (TGF-β1cells) is instrumental in promoting angiogenesis, facilitating the regrowth of endothelial cells, and contributing to the stabilization of atherosclerotic plaques. Anti-miRNA 21 can lead to plaque stabilization by decreasing inflammation and limiting the growth of smooth muscle cells while encouraging cell death, which helps prevent plaque rupture. PLGA nanoparticles can ensure high encapsulation and effective delivery of genes and viral vectors over time and can offer superior protection for their encapsulated contents, which is particularly valuable for delicate substances such as proteins and nucleic acids. This research investigates a novel combination therapy utilizing baculovirus expressing TGF-β1 gene and anti-miR-21, incorporated into gelatin-genipin polymeric nanocomposite hydrogels. The therapy demonstrates synergistic effects through dual mechanisms: promoting neo-vascularization via selective endothelial cell proliferation while inducing smooth muscle cell apoptosis to control extracellular matrix secretion and stabilize plaque. The therapeutic efficacy is evidenced by significant reduction in PTEN expression (251.1 ± 16 pg/ml compared to 375.2 ± 5.29 pg/ml in control) and enhanced angiogenic responses in the CAM assay, showing a 126.46 ± 16.62% increase in vessel length.

Endostatin-based anti-angiogenic therapy and immune modulation: mechanisms and synergistic potential in cancer treatment

2025-06-12

Jingjing Sun , Simeng Ren , QingYun Zhao +3 more | Frontiers in Immunology

Cancer remains a critical global health challenge, driven by tumor angiogenesis and immune evasion. Endostatin, a collagen XVIII-derived fragment, uniquely suppresses angiogenesis and reprograms the immunosuppressive tumor microenvironment (TME), positioning … Cancer remains a critical global health challenge, driven by tumor angiogenesis and immune evasion. Endostatin, a collagen XVIII-derived fragment, uniquely suppresses angiogenesis and reprograms the immunosuppressive tumor microenvironment (TME), positioning it as a dual-targeting therapeutic. Despite clinical advancements with recombinant human endostatin (rhEs), challenges such as transient efficacy and delivery limitations persist. Emerging strategies integrating nanotechnology, combination therapies, and immunomodulation (e.g., TAM reprogramming, immune checkpoint synergy) aim to amplify its therapeutic potential. This review synthesizes current knowledge on endostatin’s mechanisms in angiogenesis inhibition and immune modulation. It further evaluates its clinical efficacy across solid tumors and explores innovative strategies to overcome translational barriers. By dissecting technological advancements, controversies, and synergistic opportunities with radiotherapy, chemotherapy, and immunotherapy, we aim to chart a roadmap for harnessing endostatin’s full potential in redefining precision cancer therapeutics.

VEGFB167 drives tumor progression by modulating the immune microenvironment

2025-06-12

Yaowu Zheng , Quangang Chen , Haifeng Zhang +7 more | International Immunopharmacology

Engineering Osteogenic Spheroids: The Impact of Endothelial Cell Localization on Vascularization and Differentiation

2025-06-11

Yoonjoo Kang , Tae Hoon Kang , Han Ro +2 more | Advanced Healthcare Materials

Abstract Bone tissue is highly vascularized, and robust blood flow is critical for successful bone regeneration. However, the intricate architecture of bone vascular networks and the mechanisms governing their development … Abstract Bone tissue is highly vascularized, and robust blood flow is critical for successful bone regeneration. However, the intricate architecture of bone vascular networks and the mechanisms governing their development remain poorly understood, necessitating the development of in vitro models that replicate the native bone microenvironment. In this study, we investigated the influence of endothelial cell positioning within co‐cultured spheroids on vascularization and osteogenic differentiation. Human umbilical vein endothelial cells (HUVECs) and human bone marrow‐derived mesenchymal stem cells (hBMSCs) are employed to generate spheroids using two distinct co‐culture strategies: core‐shell and mixed configurations. Core‐shell spheroids are fabricated in two arrangements: hBMSCs‐core/HUVECs‐outer layer (M2H) and HUVECs‐core/hBMSCs‐outer layer (H2M). Mixed spheroids are created by co‐aggregation of HUVECs and hBMSCs. In vitro analyses revealed that endothelial cell localization significantly impacted spheroid morphology and function. Notably, M2H spheroids exhibited the highest VE‐cadherin levels, suggesting enhanced endothelial cell‐cell interactions. In Matrigel assays, M2H spheroids demonstrated superior angiogenic potential, evidenced by vascular network formation. Furthermore, we evaluated osteoblast differentiation within the spheroids to elucidate the interplay between endothelial cell positioning, vascularization, and bone development. This study provides valuable insights into the processes governing bone vascularization and offers a foundation for developing advanced tissue engineering strategies for regeneration.

Restoration of NOX4 signalling reverses endothelial colony-forming cell angiogenic dysfunction associated with experimental and clinical diabetes

2025-06-02

Karla O’Neill , Kevin Edgar , Shun Hay Pun +7 more | Stem Cell Research & Therapy

Abstract Background Progenitor endothelial colony forming cells (ECFCs) are critical for vascular homeostasis and hold therapeutic potential for ischaemic cardiovascular disease (CVD). As angiogenic capacity and efficacy within diseased tissues … Abstract Background Progenitor endothelial colony forming cells (ECFCs) are critical for vascular homeostasis and hold therapeutic potential for ischaemic cardiovascular disease (CVD). As angiogenic capacity and efficacy within diseased tissues is particularly impacted in diabetic patients, who show high incidence of ischaemic CVD, targeting of critical ECFC pathways in this setting represents an innovative focus towards enhancing intrinsic vasoreparative function. We previously reported that NADPH oxidase 4 (NOX4)-derived reactive oxygen species promote cord blood-derived ECFC (CB-ECFC) pro-angiogenic response, whilst NOX4 overexpression (OE) enhances revascularisation capacity. Here, we aimed to investigate specific influence of NOX4-dependent signalling on CB-ECFC angiogenic dysfunction observed upon exposure to both experimental and clinical diabetes to define whether NOX4 may represent a viable therapeutic target in this context. Methods CB-ECFCs were cultured in high glucose (D-glucose, 25 mmol/L) or control media (5 mmol/L) ± phorbol 12-myristate 13- acetate (PMA, 500 nmol/L) for 72 h with assessment of migratory/tubulogenic capacity and NOX4 mRNA expression (qRT-PCR). Detailed analysis of angiogenic function and signalling (Western blot, RNA sequencing) was performed in CB-ECFCs isolated from donors with gestational diabetes prior to NOX4 plasmid OE to define rescue potential and key mechanistic pathways (network analysis, proteome profiling). Statistical significance was determined using one-way ANOVA with Bonferroni post-host testing or paired/unpaired Student’s t-test, as appropriate. Results PMA-stimulated CB-ECFC migration and tube-forming capacity observed in control cells was suppressed in experimental diabetes in parallel with reduced NOX4 expression and rescued by plasmid NOX4OE. As direct evidence of clinical relevance, CB-ECFCs from gestational diabetic donors showed reduced angiogenic potential associated with attenuated NOX4, eNOS activity and downregulation of key vasoreparative signalling. Furthermore, NOX4OE rescued angiogenic function in chronically diabetic CB-ECFCs via modulation of downstream signalling involving both direct and indirect enhancement of pro-angiogenic protein expression (endoglin/SERPINE1/E2F1) linked to reduced p53 phosphorylation. Conclusions Taken together, these data indicate for the first time that reduced NOX4 expression plays a pivotal role in CB-ECFC angiogenic dysfunction linked with diabetes whilst highlighting NOX4-dependent signalling as a potential target to protect and augment their intrinsic vasoreparative capacity towards addressing current translational barriers.

Aortic cross-clamping, resection, and end-to-end anastomosis in a dog presenting with rib osteosarcoma.

2025-06-01

Géraldine Lefeuvre , Eloïse Lhuillery , Stéphane Libermann +1 more | PubMed

A 3-year-old castrated male French bulldog was presented with a mass on the left thorax that had appeared 3 wk before the consultation. Blood analyses were unremarkable. Computed tomography revealed … A 3-year-old castrated male French bulldog was presented with a mass on the left thorax that had appeared 3 wk before the consultation. Blood analyses were unremarkable. Computed tomography revealed a large heterogeneous mass arising from the 10th rib, invading the left chest, contiguous to but not infiltrating the aorta. Based on biopsies, the diagnosis was an osteoblastic osteosarcoma. Surgical treatment occurred 10 d after the computed tomographic scan and biopsies. Due to a rapid increase in the tumor's extent, the aorta was partially surrounded by the mass. Poor visibility led to an accidental aortic section with a vessel-sealing device (LigaSure; Covidien). Aortic cross-clamping allowed a 25-millimeter-long resection of the descending aorta from T7 to T11, followed by an end-to-end anastomosis. Postoperatively, the dog had temporary hind-limb ataxia for < 2 wk. At 4 mo postoperatively, the dog was euthanized due to the reappearance and degradation of new neurological symptoms associated with a left paravertebral recurrence of the tumor with slight penetration of the vertebral canal. Necropsy revealed no long-term ischemic lesions in any abdominal organ or the spine, but there was spinal cord axonal degeneration (attributed to chronic mild compression). However, the site of recurrence of the tumor-induced neurological symptoms was unrelated to the aortic resection and cross-clamping. Key clinical message: Aortic cross-clamping, resection of the descending aorta, and their neurological sequelae induced by ischemia are rarely described in nonexperimental studies in veterinary medicine. This is the first report of an 18-minute cross-clamping and a 25-millimeter-long resection of the descending aorta in which aortic cross-clamping and resection were done as an unplanned salvage procedure, and of its outcome 4 mo later, with no long-term ischemic lesions.

PATJ regulates cell stress responses and vascular remodeling post-stroke

2025-06-01

Mengqi Zhang , Wei Jiang , Kajsa Arkelius +3 more | Redox Biology

PALS1-associated tight junction (PATJ) protein is linked to metabolic disease and stroke in human genetic studies. Despite the recognized role of PATJ in cell polarization, its specific functions in metabolic … PALS1-associated tight junction (PATJ) protein is linked to metabolic disease and stroke in human genetic studies. Despite the recognized role of PATJ in cell polarization, its specific functions in metabolic disease and ischemic stroke recovery remain largely unexplored. We explored the functions of PATJ in an in vitro model and in vivo in C. elegans and mice. Using a mouse model of stroke, we found post-ischemic stroke duration-dependent increase of PATJ abundance in endothelial cells. PATJ knock-out (KO) HEK293 cells generated by CRISPR-Cas9 suggest roles for PATJ in cell proliferation, migration, mitochondrial stress response, and interactions with the Yes-associated protein (YAP)-1 signaling pathway. Notably, PATJ deletion altered YAP1 nuclear translocation. PATJ KO cells demonstrated transcriptional reprogramming based on RNA sequencing analysis, and identified dysregulation in genes central to vascular development, stress response, and metabolism, including RUNX1, HEY1, NUPR1, and HK2. Furthermore, we found that mpz-1, the homolog of PATJ, was significantly upregulated under hypoxic conditions in C. elegans. Knockdown of mpz-1 resulted in abnormal neuronal morphology and increased mortality, both of which were exacerbated by hypoxia exposure, indicating a critical protective role of PATJ/MPZ-1 in maintaining neuronal integrity and survival, particularly during oxygen deprivation stress relevant to ischemic stroke. These insights offer a new understanding of PATJ's regulatory functions within cellular and vascular physiology and help lay the groundwork for therapeutic strategies targeting PATJ-mediated pathways for stroke rehabilitation and neurovascular repair.

Multiscale Modeling Uncovers Macrophage Infiltration and TNF-α Signaling Networks for Targeting in Inflammatory Breast Cancer Tumor Emboli

2025-06-01

Pritha PAI , Christophe Van Berckelaer , Steven Van Laere +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Purpose: Inflammatory breast cancer (IBC) tumors are characterized by diffuse, clusters of cells found in dermal tissue and lymphatic vessels, known as tumor emboli. This study investigates the interaction between … Purpose: Inflammatory breast cancer (IBC) tumors are characterized by diffuse, clusters of cells found in dermal tissue and lymphatic vessels, known as tumor emboli. This study investigates the interaction between tumor emboli and the tumor immune microenvironment (TiME) that can foster survival signaling. Experimental Design: Spatial immunophenotyping was performed on clinical IBC samples. Ex vivo tumor emboli were generated from patient-derived cell lines cultured in a lymphatic-like platform and subjected to transcriptomic and proteomic analysis. A transgenic CX3cr1GFP murine model was generated for visualization of macrophages and tumor emboli within the TiME via a surgically implanted window chamber, enabling intravital imaging and targeting. Results: Gene and protein analysis of tumor emboli cultures compared to 2D monolayer cultures revealed upregulation of TNFR signaling networks, CXCL8, and immune cell chemotaxis genes. Spatial immunophenotyping of IBC patient tumors demonstrated high levels of CD163+ tumor-associated macrophages (TAMs). Furthermore, intravital imaging of CX3cr1GFP mice confirmed macrophage movement toward tumor cell clusters. Finally, targeting macrophage-associated TNF-α-signaling using Birinapant, a SMAC mimetic, inhibited the tumor emboli phenotype in vivo. Conclusions: This study, the first to our knowledge, identifies TNFα signaling and macrophage infiltration in IBC tumor emboli. Strategies targeting TNFα signaling to induce cell death and reduce macrophage influence has the potential to improve IBC outcomes.

Design, Synthesis, In Silico and In Vitro Studies Urea Derivatives as VEGFR-2 Inhibitors

2025-06-01

Hayder Ghanim Chfat , Ahmed Wheed Radhi , Ali Jabbar Radhi +1 more | Journal of Molecular Structure

Mesangial angiogenesis and interstitial eosinophilic infiltration in diabetic nephropathy are associated with elevated CD248 expression

2025-06-01

Xiangmeng Li , Jiao Zhang , Ying Wang +5 more | Renal Failure

To investigate the factors associated with angiogenesis within the glomerular mesangial area and interstitial eosinophilic infiltration in diabetic nephropathy (DN). The NCBI database identified differentially expressed genes (DEGs) in DN … To investigate the factors associated with angiogenesis within the glomerular mesangial area and interstitial eosinophilic infiltration in diabetic nephropathy (DN). The NCBI database identified differentially expressed genes (DEGs) in DN patients linked to angiogenesis and inflammation. Bioinformatics analyzed these genes and mechanisms. In vivo (DN patients and db/db mice) and in vitro experiments explored glomerular mesangial angiogenesis and interstitial eosinophilic infiltration mechanisms. Twenty-five independent DEGs associated with DN were identified, and CD248 was associated with vessel formation and inflammatory cells. Biological analysis suggested CD248 mainly promoted vessel formation and eosinophilic infiltration via VEGFC and CCL-5, respectively. In DN patients, neovascularization with CD31-positive endothelial cells was observed in the mesangial regions, which was accompanied by increased expression of CD248 and VEGFC. Eosinophilic infiltration was observed in the renal interstitium, and the degree of eosinophilic infiltration was positively correlated with the intensity of CD248 expression. Serial section analysis revealed that areas with increased eosinophilic infiltration exhibited stronger infiltration of CD3-positive cells and elevated CCL-5 expression. Similar findings were discovered in the db/db mice, with WB results demonstrating higher expression levels of CD248, CCL-5, and VEGFC in the renal tissues of db/db mice compared with m/m mice. In vitro, CD248 expression is low in mesangial cells, but increased under high-glucose/LPS. CD248 siRNA reduced high-glucose/LPS-induced VEGFC/CCL-5. In DN, CD248 may contribute to mesangial angiogenesis and renal interstitial eosinophilic infiltration; these pathological processes may be associated with the elevated expressions of VEGFC and CCL-5, respectively.

Revolutionizing Treatment of Peripheral Arterial Disease through Allogenic Endothelial Progenitor Cells (EPCs)

2025-06-01

Huiyuan Zhang , Hui Shi , Wenjuan Zhang +7 more | Metabolism

Investigating endothelial cell transduction and hexon:PF4 binding of ChAdOx1 in the context of VITT

2025-06-01

Charlotte Lovatt , Lars Frängsmyr , Emma A. Swift +2 more | Journal of Thrombosis and Haemostasis

Vaccines against SARS-CoV2 have been essential in controlling COVID-19 related mortality and have saved millions of lives. Adenoviral (Ad) based vaccines been integral part in this vaccine campaign, with licensed … Vaccines against SARS-CoV2 have been essential in controlling COVID-19 related mortality and have saved millions of lives. Adenoviral (Ad) based vaccines been integral part in this vaccine campaign, with licensed vaccines based on the simian Y25 isolate (Vaxzevria, Astrazeneca) and human Ad type 26 (Jcovden, Janssen) widely adopted. As part of the largest global vaccination programme ever undertaken, cases of vaccine-induced thrombotic thrombocytopenia (VITT) have been described in approximately 1:200,000 vaccinees administered with Ad based SARS-CoV2 vaccines. The mechanism underpinning these adverse events remain to be completely delineated, but is characterised by elevated autoantibodies against PF4 which, in complex with PF4, cluster, bind FcγRIIa on platelets and induce thrombus formation. Here we investigated the ability of ChAdOx1 to transduce and activate endothelial cells (EC). Using protein sequence alignment tools and in vitro transduction assays, the ability of ChAdOx1 to infect EC was assessed. Furthermore, the ability of ChAdOx1 infection to activate EC was determined. Finally, using surface plasmon resonance we assessed the electrostatic interactions between the ChAdOx1 hexon and PF4. Despite lacking the primary cell entry receptor, Coxsackie and Adenovirus Receptor (CAR), ChAdOx1 efficiently transduced EC in a CAR-independent manner. This transduction did not result in EC activation. Purified hexon protein from ChAdOx1 preps did, however, bind PF4 with a similar affinity to that previously reported for the whole ChAdOx1 capsid. These data confirm the need to develop non-PF4 binding adenoviral capsids and assess their potential to mitigate adverse events associated with VITT.

Coaxial printing of slow-release heparin-binding epidermal growth factor scaffold to avoid the occurrence of intrauterine adhesions

2025-06-01

Jing He , Zeming Gu , Qianqian Wei +4 more | Acta Biomaterialia

Rapid generation of functional vascular organoids via simultaneous transcription factor activation of endothelial and mural lineages

2025-06-01

Liyan Gong , Yadong Zhang , Yonglin Zhu +7 more | Cell stem cell

POS0010 A Novel Therapeutic Effect of VEGF Decoy Receptor Fusion Protein, VEGF-Grab, in Chronic Inflammatory Diseases

2025-06-01

H.Y. Lee , Yan Lee , K.G. Lee +7 more | Annals of the Rheumatic Diseases

Correlation of VEGF +405C/G Polymorphism with Gastrointestinal Tract Cancers Risk: An Updated Meta-Analysis

2025-06-01

Sukhpreet Kaur Walia , Vasudha Sambyal , Kamlesh Guleria | Asian Pacific Journal of Cancer Prevention

The functional polymorphisms of VEGF can affect different cellular processes and play a major role in angiogenesis and tumor development. Several case-control studies have explored the association of VEGF +405C/G … The functional polymorphisms of VEGF can affect different cellular processes and play a major role in angiogenesis and tumor development. Several case-control studies have explored the association of VEGF +405C/G polymorphism with GIT cancer risk, however, the results were inconsistent. Therefore, the meta-analysis was conducted to clarify the association. Based on the inclusion and exclusion criteria, relevant data were extracted from PubMed, Google Scholar, Web of Science and Science Direct. Twenty three studies comprising 5,656 cases and 6,319 healthy controls were included in the present meta-analysis and the data was analysed by using online MetaGenyo software. In the present study, no significant association was found in any of the genetic models in overall analysis as well as when data was stratified according to the ethnicity (p>0.05). After performing sub-group analysis on the basis of cancer type, significant association was found with increased risk of developing esophageal cancer under allele contrast, recessive, GG vs. CC and GG vs. GC models (p<0.05). Under overdominant model, VEGF +405C/G polymorphism was significantly associated with decreased risk of developing esophageal cancer (p=0.017) and GG vs. GC model showed a significant association with the risk of developing colorectal cancer (p=0.047) and pancreatic cancer (p=0.010). However, GC vs. CC model showed that VEGF +405C/G polymorphism was significantly associated with reduced risk of pancreatic cancer (p=0.039). The present updated meta-analysis suggested that VEGF +405C/G polymorphism may serve as a biomarker for determining an individual's risk of esophageal, colorectal and pancreatic cancer.

Aptamer/Antibody-Based and Amplified Lateral Flow Assays for Detection of Vascular Endothelial Growth Factor 165

2025-06-01

Chenjing Fan , Yu-Shi Liu , Xiushuang Fan +4 more | CHINESE JOURNAL OF ANALYTICAL CHEMISTRY (CHINESE VERSION)

Activin A prevents hyper-responsiveness to VEGF in pathological blood vessels by perturbing the trafficking of activated VEGFR2

2025-06-01

Basma Baccouche , Maximilian McCann , Rajasekar Janani +3 more | American Journal Of Pathology

While quality-of-life compromising afflictions such as diabetic retinopathy (DR) are driven by vascular endothelial growth factor (VEGF), there is a growing appreciation that the concentration of VEGF is not the … While quality-of-life compromising afflictions such as diabetic retinopathy (DR) are driven by vascular endothelial growth factor (VEGF), there is a growing appreciation that the concentration of VEGF is not the only influencer of vascular dysfunction within the retina. Activin A (activin), a ligand of the transforming growth factor β superfamily (TGF-β), attenuated VEGF-induced VE-cadherin disorganization, pore formation, and permeability of primary human retinal endothelial cells (HRECs). Efforts to further investigate the mechanism of this phenomenon revealed that activin reduced the expression of Rab11, which was required for the activin effect. The activin effect was not observed in cells with suppressed expression of the endosomally-localized protein tyrosine phosphatase (PTP1b), whereas PTPs present on the plasma membrane were dispensable. Activin attenuated VEGF-mediated phosphorylation of VEGF receptor 2 (VEGFR2) at 30 min and longer post-stimulation time points. Together these data support the concept that activin suppressed VEGF-induced barrier relaxation by perturbing trafficking of activated VEGFR2. This activin-based suppression of responsiveness to VEGF was compromised in the endothelium of pathological blood vessels from patients who developed end-stage proliferative diabetic retinopathy (PDR). This defect rendered HRECs hyper-responsive to VEGF and was not observed in retinal vessels of diabetic mice, which do not develop the angiogenic forms of DR. These data provide novel insights regarding the pathogenesis of PDR in patients.

The concentration of serum Thrombospondin-1 is correlated with the severity of osteoarthritis in mice and humans

2025-05-30

Xianda Che , Xiaochun Wei | Osteoarthritis and Cartilage

Association of VEGFA Gene Polymorphisms with the Susceptibility of Coronary Heart Disease in the Chinese Han Population

2025-05-30

Kang Huang , Shijuan Lu , Yilei Zhou +4 more | Cardiovascular Toxicology

In Vitro Models of Vasculogenesis for High-Throughput Applications

2025-05-29

Jens Friedrichs , Yanuar Dwi Putra Limasale , Maximilian Fusenig +4 more | WORLD SCIENTIFIC eBooks

SECN-15: A novel treatment option for patients with checkpoint inhibitor–resistant tumors by targeting Neuropilin-1 with antisense oligonucleotides.

2025-05-28

André Maaske , Anne Sadewasser , Sven Michel +7 more

2580 Background: SECN-15 is a high-affinity antisense oligonucleotide (ASO) targeting Neuropilin-1 (NRP1), a transmembrane protein that exerts a variety of protumorigenic functions by interacting with various receptors and ligands. NRP1 … 2580 Background: SECN-15 is a high-affinity antisense oligonucleotide (ASO) targeting Neuropilin-1 (NRP1), a transmembrane protein that exerts a variety of protumorigenic functions by interacting with various receptors and ligands. NRP1 contributes to an immunosuppressive microenvironment, tumor growth, metastasis, and neoangiogenesis. The recent success of bispecific antibodies targeting PD-1/PD-L1 and VEGF such as ivonescimab has highlighted the potential of combining checkpoint inhibitors with anti-angiogenic approaches. Consequently, NRP1 represents a highly attractive target for treating patients with tumors that are resistant to or insufficiently responsive to checkpoint inhibitor therapies, such as gastric (GC) and breast cancer, where high NRP1 expression correlates with poor prognosis. Methods: NRP1-specific locked nucleic acid (LNA)-modified ASOs were identified using our OligoCreator platform. We assessed in vivo anti-tumor efficacy after systemic administration in various mouse tumor models as monotherapy and in combination with checkpoint inhibitors. Target downregulation was analyzed in tissues and in plasma by measuring soluble NRP1. Cell composition and transcriptome changes in tumors were analyzed using flow cytometry and RNA sequencing. Exaggerated pharmacology was investigated in a 28 non-GLP tolerability study in mice. In silico analyses of patient transcriptomics data were performed to prioritize indications for the upcoming Phase I/II clinical trial. Results: Systemic administration of NRP1-specific ASOs resulted in robust knockdown in tumors across various cell types, including macrophages and T cells. Soluble NRP1 levels were reduced in treated animals, serving as a target engagement biomarker. Tumor growth was delayed in the monotherapy setting, with several animals showing complete responses. Combining NRP1-specific ASOs with checkpoint inhibitors enhanced efficacy in models where checkpoint inhibitors alone had limited activity. Transcriptomic analysis showed upregulation of inflammatory genes and downregulation of extracellular matrix organization genes. No adverse effects were observed from persistent NRP1 downregulation in non-tumor-bearing mice. In silico analyses revealed that NRP1 expression is negatively associated with survival and increases in advanced GC stages. GC was selected as one of the priority indications for the upcoming Phase I/II clinical trial to investigate SECN-15's safety and efficacy as monotherapy and in combination with PD-1 blocking antibodies. Conclusions: Targeting NRP1 with ASOs is a promising therapeutic strategy for solid cancers. Combining NRP1 ASOs with ICIs significantly enhances anti-tumor efficacy, potentially overcoming current ICI therapy limitations. IND-enabling studies are underway to advance SECN-15 into clinical development.