Neuropilin-1 regulates attachment in human endothelial cells independently of vascular endothelial growth factor receptor-2

AbstractNeuropilin-1 (NRP-1) is a type 1 membrane protein that binds the axon guidance factors belonging to the class-3 semaforin family. In endothelial cells, NRP-1 serves as a co-receptor for vascular endothelial growth factor (VEGF) and regulates VEGF receptor 2 (VEGFR-2)–dependent angiogenesis. Although gene-targeting studies documenting embryonic lethality in NRP-1 null mice have demonstrated a critical role for NRP-1 in vascular development, the activities of NRP-1 in mature endothelial cells have been incompletely defined. Using RNA interference-mediated silencing of NRP-1 or VEGFR-2 in primary human endothelial cells, we confirm that NRP-1 modulates VEGFR-2 signaling-dependent mitogenic functions of VEGF. Importantly, we now show that NRP-1 regulates endothelial cell adhesion to extracellular matrix proteins independently of VEGFR-2. Based on its dual role as an enhancer of VEGF activity and a mediator of endothelial cell adhesiveness described here, NRP-1 emerges as a promising molecular target for the development of antiangiogenic drugs.

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Inhibition of vascular endothelial growth factor receptor 2–mediated endothelial cell activation by Axl tyrosine kinase receptor

Blood ◽

10.1182/blood-2004-04-1469 ◽

2005 ◽

Vol 105 (5) ◽

pp. 1970-1976 ◽

Cited By ~ 67

Author(s):

Margherita Gallicchio ◽

Stefania Mitola ◽

Donatella Valdembri ◽

Roberto Fantozzi ◽

Brian Varnum ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Endothelial Cell ◽

Growth Factor ◽

Tyrosine Kinase ◽

Tyrosine Phosphatase ◽

Tyrosine Kinase Receptor ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Endothelial Growth Factor

AbstractGAS6, the product of a growth arrest specific (GAS) gene, is the ligand of the tyrosine kinase receptor Axl. GAS6 and Axl are both expressed in endothelial cells, where they are involved in many processes such as leukocyte transmigration through capillaries and neointima formation in injured vessels. Here, we show that Axl stimulation by GAS6 results in inhibition of the ligand-dependent activation of vascular endothelial growth factor (VEGF) receptor 2 and the consequent activation of an angiogenic program in vascular endothelial cells. GAS6 inhibits chemotaxis of endothelial cells stimulated by VEGF-A isoforms, but not that triggered by fibroblast growth factor-2 or hepatocyte growth factor. Furthermore, it inhibits endothelial cell morphogenesis on Matrigel and VEGF-A–dependent vascularization of chick chorion allantoid membrane. GAS6 activates the tyrosine phosphatase SHP-2 (SH2 domain-containing tyrosine phosphatase 2), which is instrumental in the negative feedback exerted by Axl on VEGF-A activities. A dominant-negative SHP-2 mutant, in which Cys 459 is substituted by Ser, reverted the effect of GAS6 on stimulation of VEGF receptor 2 and endothelial chemotaxis triggered by VEGF-A. These studies provide the first demonstration of a cross talk between Axl and VEGF receptor 2 and add new information on the regulation of VEGF-A activities during tissue vascularization.

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The Vascular Endothelial Growth Factor (VEGF)/VEGF Receptor 2 Pathway Is Critical for Blood Vessel Survival in Corpora Lutea of Pregnancy in the Rodent

Endocrinology ◽

10.1210/en.2004-0765 ◽

2005 ◽

Vol 146 (3) ◽

pp. 1301-1311 ◽

Cited By ~ 58

Author(s):

Samuel A. Pauli ◽

Hongyan Tang ◽

Jeff Wang ◽

Peter Bohlen ◽

Robert Posser ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cell ◽

Growth Factor ◽

Life Span ◽

Critical Role ◽

Corpora Lutea ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Luteal Function ◽

Endothelial Growth Factor

The vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR-2) pathway regulates proliferation, survival, and permeability of vasculature. This pathway is active during the formation of a corpus luteum, a highly vascularized, endocrine organ with a short life span during the nonpregnant state. In the pregnant state, the life span of corpora lutea is much longer because they play a critical role in supporting pregnancy development. We hypothesized that the VEGF/VEGFR-2 pathway plays a critical role in regulating angiogenic events in the corpora lutea of pregnancy. Injection of the neutralizing anti-VEGFR-2 antibody DC101 (ImClone Systems, Inc., New York, NY) on embryonic d 3.5 (preimplantation) or 6.5 (postimplantation) disrupts function of the corpora lutea of pregnancy in CD1 mice, as evidenced by a decrease in organ size, regression of luteal vessels, and a fall in progesterone secretion within 24 h postinjection. Inhibition of the VEGFR-2 caused removal of endothelial cells, mostly through endothelial cell detachment from the vascular basement membrane. Luteal steroid-producing epithelial cells were eliminated through apoptosis secondary to vasculature becoming dysfunctional. Disruption of luteal function caused arrest of embryonic development. The effect of antibody is specific to the ovary, because pregnancy progresses normally in ovariectomized, progesterone-replaced animals treated with anti-VEGFR-2 antibody. Embryonic blood vessels were not affected directly by the antibody, because it did not reach the embryo. Administration of an antibody against VE-cadherin (E4G10), which specifically blocks endothelial proliferation, did not disrupt luteal function and pregnancy development. Thus, VEGFR-2-mediated endothelial cell signals are critical to maintain functionality of luteal blood vessels during pregnancy. Potential clinical applications of inhibitors of the VEGF/VEGFR-2 pathway include emergency contraception and medical treatment of ectopic and abnormal intrauterine pregnancies.

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Faculty Opinions recommendation of MicroRNA-10 regulates the angiogenic behavior of zebrafish and human endothelial cells by promoting vascular endothelial growth factor signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717957529.793461935 ◽

2012 ◽

Author(s):

Paul Evans ◽

Jovana Serbanovic-Canic

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Growth Factor Signaling ◽

Vascular Endothelial ◽

Human Endothelial Cells ◽

Endothelial Growth Factor

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Mid-luteal angiogenesis and function in the primate is dependent on vascular endothelial growth factor

Journal of Endocrinology ◽

10.1677/joe.0.1680409 ◽

2001 ◽

Vol 168 (3) ◽

pp. 409-416 ◽

Cited By ~ 50

Author(s):

SE Dickson ◽

R Bicknell ◽

HM Fraser

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Endothelial Cell ◽

Growth Factor ◽

Luteal Phase ◽

Smooth Muscle Actin ◽

Proliferation Index ◽

Endothelial Cell Proliferation ◽

Vascular Endothelial ◽

Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is essential for the angiogenesis required for the formation of the corpus luteum; however, its role in ongoing luteal angiogenesis and in the maintenance of the established vascular network is unknown. The aim of this study was to determine whether VEGF inhibition could intervene in ongoing luteal angiogenesis using immunoneutralisation of VEGF starting in the mid-luteal phase. In addition, the effects on endothelial cell survival and the recruitment of periendothelial support cells were examined. Treatment with a monoclonal antibody to VEGF, or mouse gamma globulin for control animals, commenced on day 7 after ovulation and continued for 3 days. Bromodeoxyuridine (BrdU), used to label proliferating cells to obtain a proliferation index, was administered one hour before collecting ovaries from control and treated animals. Ovarian sections were stained using antibodies to BrdU, the endothelial cell marker, CD31, the pericyte marker, alpha-smooth muscle actin, and 3' end DNA fragments as a marker for apoptosis. VEGF immunoneutralisation significantly suppressed endothelial cell proliferation and the area occupied by endothelial cells while increasing pericyte coverage and the incidence of endothelial cell apoptosis. Luteal function was markedly compromised by anti-VEGF treatment as judged by a 50% reduction in plasma progesterone concentration. It is concluded that ongoing angiogenesis in the mid-luteal phase is primarily driven by VEGF, and that a proportion of endothelial cells of the mid-luteal phase vasculature are dependent on VEGF support.

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p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells

Oncogene ◽

10.1038/sj.onc.1201380 ◽

1997 ◽

Vol 15 (18) ◽

pp. 2169-2177 ◽

Cited By ~ 598

Author(s):

Simon Rousseau ◽

François Houle ◽

Jacques Landry ◽

Jacques Huot

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Cell Migration ◽

Growth Factor ◽

P38 Map Kinase ◽

Vascular Endothelial ◽

Human Endothelial Cells ◽

Actin Reorganization ◽

Kinase Activation ◽

Endothelial Growth Factor

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Bone Morphogenetic Protein 7 Increased Vascular Endothelial Growth Factor (VEGF)-A Expression in Human Granulosa Cells and VEGF Receptor Expression in Endothelial Cells

Reproductive Sciences ◽

10.1177/1933719113503411 ◽

2013 ◽

Vol 21 (4) ◽

pp. 477-482 ◽

Cited By ~ 20

Author(s):

Ikumi Akiyama ◽

Osamu Yoshino ◽

Yutaka Osuga ◽

Jia Shi ◽

Miyuki Harada ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Receptor Expression ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Bone Morphogenetic Protein 7 ◽

Human Granulosa Cells ◽

Morphogenetic Protein ◽

Endothelial Growth Factor

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Andes Virus Disrupts the Endothelial Cell Barrier by Induction of Vascular Endothelial Growth Factor and Downregulation of VE-Cadherin

Journal of Virology ◽

10.1128/jvi.01405-10 ◽

2010 ◽

Vol 84 (21) ◽

pp. 11227-11234 ◽

Cited By ~ 74

Author(s):

Punya Shrivastava-Ranjan ◽

Pierre E. Rollin ◽

Christina F. Spiropoulou

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Endothelial Cell ◽

Growth Factor ◽

Virus Replication ◽

Cell Permeability ◽

Hantavirus Infection ◽

Vascular Endothelial ◽

Andes Virus ◽

Endothelial Growth Factor

ABSTRACT Hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS) are severe diseases associated with hantavirus infection. High levels of virus replication occur in microvascular endothelial cells but without a virus-induced cytopathic effect. However, virus infection results in microvascular leakage, which is the hallmark of these diseases. VE-cadherin is a major component of adherens junctions, and its interaction with the vascular endothelial growth factor (VEGF) receptor, VEGF-R2, is important for maintaining the integrity of the endothelial barrier. Here we report that increased secreted VEGF and concomitant decreased VE-cadherin are seen at early times postinfection of human primary lung endothelial cells with an HPS-associated hantavirus, Andes virus. Furthermore, active virus replication results in increased permeability and loss of the integrity of the endothelial cell barrier. VEGF binding to VEGF-R2 is known to result in dissociation of VEGF-R2 from VE-cadherin and in VE-cadherin activation, internalization, and degradation. Consistent with this, we showed that an antibody which blocks VEGF-R2 activation resulted in inhibition of the Andes virus-induced VE-cadherin reduction. These data implicate virus induction of VEGF and reduction in VE-cadherin in the endothelial cell permeability seen in HPS and suggest potential immunotherapeutic targets for the treatment of the disease.

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