scholarly journals 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 ◽  
2005 ◽  
Vol 146 (3) ◽  
pp. 1301-1311 ◽  
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.

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

Blood ◽  
2005 ◽  
Vol 105 (5) ◽  
pp. 1992-1999 ◽  
Author(s):  
Matilde Murga ◽  
Oscar Fernandez-Capetillo ◽  
Giovanna Tosato
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Critical Role ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Human Endothelial Cells ◽  
Neuropilin 1 ◽  
Endothelial Growth Factor

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.

scholarly journals Viral Vascular Endothelial Growth Factor Plays a Critical Role in Orf Virus Infection

2000 ◽  
Vol 74 (22) ◽  
pp. 10699-10706 ◽  
Author(s):  
Loreen J. Savory ◽  
Steven A. Stacker ◽  
Stephen B. Fleming ◽  
Brian E. Niven ◽  
Andrew A. Mercer
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Virus Infection ◽  
Vascular Endothelial Cells ◽  
Critical Role ◽  
Skin Lesions ◽  
Orf Virus ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

ABSTRACT Infection by the parapoxvirus orf virus causes proliferative skin lesions in which extensive capillary proliferation and dilation are prominent histological features. This infective phenotype may be linked to a unique virus-encoded factor, a distinctive new member of the vascular endothelial growth factor (VEGF) family of molecules. We constructed a recombinant orf virus in which the VEGF-like gene was disrupted and show that inactivation of this gene resulted in the loss of three VEGF activities expressed by the parent virus: mitogenesis of vascular endothelial cells, induction of vascular permeability, and activation of VEGF receptor 2. We used the recombinant orf virus to assess the contribution of the viral VEGF to the vascular response seen during orf virus infection of skin. Our results demonstrate that the viral VEGF, while recognizing a unique profile of the known VEGF receptors (receptor 2 and neuropilin 1), is able to stimulate a striking proliferation of blood vessels in the dermis underlying the site of infection. Furthermore, the data demonstrate that the viral VEGF participates in promoting a distinctive pattern of epidermal proliferation. Loss of a functional viral VEGF resulted in lesions with markedly reduced clinical indications of infection. However, viral replication in the early stages of infection was not impaired, and only at later times did it appear that replication of the recombinant virus might be reduced.

Tumor-induced endothelial cell activation: role of vascular endothelial growth factor

2004 ◽  
Vol 286 (5) ◽  
pp. C1170-C1176 ◽  
Author(s):  
M. Ángeles Castilla ◽  
Fernando Neria ◽  
Guadalupe Renedo ◽  
Daniel S. Pereira ◽  
Francisco R. González-Pacheco ◽  
...  
Keyword(s):  
Gene Expression ◽  
Vascular Endothelial Growth Factor ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Protein Kinase ◽  
Cell Line ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Osteoblastic Cell Line ◽  
Endothelial Growth Factor

Proangiogenic, proliferative effects of tumors have been extensively characterized in subconfluent endothelial cells (EC), but results in confluent, contact-inhibited EC are critically lacking. The present study examined the effect of tumor-conditioned medium (CM) of the malignant osteoblastic cell line MG63 on monolayer, quiescent bovine aorta EC. MG63-CM and MG63-CM + CoCl2 significantly increased EC survival in serum-starved conditions, without inducing EC proliferation. Furthermore, MG63-CM and MG63-CM + CoCl2, both containing high amounts of vascular endothelial growth factor (VEGF), induced relevant phenotypic changes in EC (all P < 0.01) involving increase of nucleoli/chromatin condensations, nucleus-to-cytosol ratio, capillary-like vacuolated structures, vessel-like acellular areas, migration through Matrigel, growth advantage in reseeding, and factor VIII content. All these actions were significantly inhibited by VEGF and VEGF receptor (VEGFR2) blockade. Of particular importance, a set of similar effects were detected in a human microvascular endothelial cell line (HMEC). With regard to gene expression, incubation with MG63-CM abolished endogenous VEGF mRNA and protein but induced a clear-cut increase in VEGFR2 mRNA expression in EC. In terms of mechanism, MG63-CM activates protein kinase B (PKB)/Akt, p44/p42-mitogen-activated protein kinase (MAPK)-mediated pathways, as suggested by both inhibition and phosphorylation experiments. In conclusion, tumor cells activate confluent, quiescent EC, promoting survival, phenotypic, and gene expression changes. Of importance, VEGF antagonism converts MG63-CM from protective to EC-damaging effects.

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

Blood ◽  
2005 ◽  
Vol 105 (5) ◽  
pp. 1970-1976 ◽  
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.

scholarly journals Role of Vascular Endothelial Growth Factor in Maintenance of Pregnancy in Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (2) ◽  
pp. 900-910 ◽  
Author(s):  
Yoshiko Wada ◽  
Hiromi Ozaki ◽  
Naomichi Abe ◽  
Asami Mori ◽  
Kenji Sakamoto ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Critical Role ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Maternal Circulation ◽  
Sequence Of Events ◽  
High Level ◽  
Rats And Mice ◽  
Endothelial Growth Factor

It is well known that withdrawal of progesterone from the maternal circulation is a critical stimulus to parturition in rodents, such as rats and mice. However, mechanisms that determine the timing of progesterone withdrawal are not completely understood. In the present study, we examined whether the vascular endothelial growth factor (VEGF) system in the corpus luteum (CL) contributes to the regulation of circulating progesterone levels and acts as a determinant of the timing of parturition in mice. We found that reduction in the expression levels of VEGF and VEGF receptor-2 in the CL precedes the impairment of luteal circulation and a series of events leading to parturition (i.e., reduction of plasma progesterone, enhancement of myometrium contractility, and onset of parturition). Blocking of VEGF signaling by using the inhibitor of VEGFR tyrosine kinase KRN633 at mid-pregnancy caused a similar sequence of events and induced preterm birth. These results suggest that the VEGF system in the CL plays a critical role in maintaining a high level of circulating progesterone, and determining the timing of parturition in mice.

scholarly journals Expression and localization of vascular endothelial growth factor and its receptors in pig corpora lutea during the oestrous cycle

Reproduction ◽  
2003 ◽  
pp. 393-405 ◽  
Author(s):  
U Boonyaprakob ◽  
JE Gadsby ◽  
V Hedgpeth ◽  
P Routh ◽  
GW Almond
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Northern Blot ◽  
Luteal Phase ◽  
Northern Blot Analysis ◽  
Corpora Lutea ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Vegf Mrna ◽  
Endothelial Growth Factor

Expression and localization of mRNAs for vascular endothelial growth factor (VEGF), VEGF receptor 1 (Flt) and VEGF receptor 2 (KDR) (VEGFR-1 and VEGFR-2, respectively) were investigated in pig corpora lutea. Northern blot analysis of total RNA indicated hybridization of pig VEGF, VEGFR-1 and VEGFR-2 cDNA probes to mRNA transcripts of approximately 3.9, 7.0 and 5.0 kb, respectively. The expression of mRNAs for VEGF and its receptors during the luteal phase (days 4, 7, 10, 13 and 15 after the onset of oestrus) were assessed by northern blot analysis, and hybridization signals were normalized to expression of pig 18S rRNA. Relative hybridization signals of expression of VEGF mRNA appeared to be constant; however, expression of VEGFR-1 mRNA was low on day 4, increased on day 7, and was higher on days 10, 13 and 15 (P<0.05, compared with day 4). In contrast, no changes in expression of mRNA for VEGFR-2 were evident on days 4-13, but a decrease was detected (P<0.05) at day 15. In situ hybridization revealed that VEGF mRNA was localized predominantly in large luteal cells, whereas both VEGFR-1 and VEGFR-2 were localized to small cells. These data indicate that the VEGF system may be involved in the regulation of luteal vasculature throughout the lifespan of the corpus luteum. Although the expression of VEGF mRNA was unchanged during the luteal phase, variations in the expression of VEGFR-1 and VEGFR-2 mRNAs indicate that differential regulation of expression of the VEGF receptors may play a role in the control of VEGF-mediated vascular growth at different phases of development and maturation of the pig corpus luteum.

scholarly journals Role of Vascular Endothelial Growth Factor (VEGF) in Human Embryo Implantation: Clinical Implications

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 253
Author(s):  
Xi Guo ◽  
Hong Yi ◽  
Tin Chiu Li ◽  
Yu Wang ◽  
Huilin Wang ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Recurrent Miscarriage ◽  
Embryo Implantation ◽  
Critical Role ◽  
Angiogenic Factor ◽  
Vascular Endothelial ◽  
Underlying Mechanisms ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is a well-known angiogenic factor that plays a critical role in various physiological and pathological processes. VEGF also contributes to the process of embryo implantation by enhancing embryo development, improving endometrial receptivity, and facilitating the interactions between the developing embryo and the endometrium. There is a correlation between the alteration of VEGF expression and reproductive failure, including recurrent implantation failure (RIF) and recurrent miscarriage (RM). In order to clarify the role of VEGF in embryo implantation, we reviewed recent literature concerning the expression and function of VEGF in the reproductive system around the time of embryo implantation and we provide a summary of the findings reported so far. We also explored the effects and the possible underlying mechanisms of action of VEGF in embryo implantation.

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