scholarly journals The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching

2008 ◽  
Vol 181 (5) ◽  
pp. 847-858 ◽  
Author(s):  
Nicholas C. Kappas ◽  
Gefei Zeng ◽  
John C. Chappell ◽  
Joseph B. Kearney ◽  
Surovi Hazarika ◽  
...  
Keyword(s):  
Blood Vessel ◽  
Embryonic Stem ◽  
Branching Morphogenesis ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Endothelial Proliferation ◽  
Integrated Regulation ◽  
Set Up ◽  
Endothelial Growth Factor

Blood vessel formation requires the integrated regulation of endothelial cell proliferation and branching morphogenesis, but how this coordinated regulation is achieved is not well understood. Flt-1 (vascular endothelial growth factor [VEGF] receptor 1) is a high affinity VEGF-A receptor whose loss leads to vessel overgrowth and dysmorphogenesis. We examined the ability of Flt-1 isoform transgenes to rescue the vascular development of embryonic stem cell–derived flt-1−/− mutant vessels. Endothelial proliferation was equivalently rescued by both soluble (sFlt-1) and membrane-tethered (mFlt-1) isoforms, but only sFlt-1 rescued vessel branching. Flk-1 Tyr-1173 phosphorylation was increased in flt-1−/− mutant vessels and partially rescued by the Flt-1 isoform transgenes. sFlt-1–rescued vessels exhibited more heterogeneous levels of pFlk than did mFlt-1–rescued vessels, and reporter gene expression from the flt-1 locus was also heterogeneous in developing vessels. Our data support a model whereby sFlt-1 protein is more efficient than mFlt-1 at amplifying initial expression differences, and these amplified differences set up local discontinuities in VEGF-A ligand availability that are important for proper vessel branching.

scholarly journals VEGF-A-Cleavage by FSAP and Inhibition of Neo-Vascularization

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1396 ◽  
Author(s):  
Özgür Uslu ◽  
Joerg Herold ◽  
Sandip M. Kanse
Keyword(s):  
Growth Factor ◽  
Tissue Injury ◽  
Factor Vii ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
The Matrix ◽  
Endothelial Growth Factor

Alternative splicing leads to the secretion of multiple forms of vascular endothelial growth factor-A (VEGF-A) that differ in their activity profiles with respect to neovascularization. FSAP (factor VII activating protease) is the zymogen form of a plasma protease that is activated (FSAPa) upon tissue injury via the release of histones. The purpose of the study was to determine if FSAPa regulates VEGF-A activity in vitro and in vivo. FSAP bound to VEGF165, but not VEGF121, and VEGF165 was cleaved in its neuropilin/proteoglycan binding domain. VEGF165 cleavage did not alter its binding to VEGF receptors but diminished its binding to neuropilin. The stimulatory effects of VEGF165 on endothelial cell proliferation, migration, and signal transduction were not altered by FSAP. Similarly, proliferation of VEGF receptor-expressing BAF3 cells, in response to VEGF165, was not modulated by FSAP. In the mouse matrigel model of angiogenesis, FSAP decreased the ability of VEGF165, basic fibroblast growth factor (bFGF), and their combination, to induce neovascularization. Lack of endogenous FSAP in mice did not influence neovascularization. Thus, FSAP inhibited VEGF165-mediated angiogenesis in the matrigel model in vivo, where VEGF’s interaction with the matrix and its diffusion are important.

scholarly journals Modulation of VEGFR-2–mediated endothelial-cell activity by VEGF-C/VEGFR-3

Blood ◽  
2003 ◽  
Vol 101 (4) ◽  
pp. 1367-1374 ◽  
Author(s):  
Kazuyoshi Matsumura ◽  
Masanori Hirashima ◽  
Minetaro Ogawa ◽  
Hajime Kubo ◽  
Hiroshi Hisatsune ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Activity ◽  
Embryonic Stem ◽  
Cellular Level ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Vascular Integrity ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3), a receptor for VEGF-C, was shown to be essential for angiogenesis as well as for lymphangiogenesis. Targeted disruption of theVEGFR-3 gene in mice and our previous study using an antagonistic monoclonal antibody (MoAb) for VEGFR-3 suggested that VEGF-C/VEGFR-3 signals might be involved in the maintenance of vascular integrity. In this study we used an in vitro embryonic stem (ES) cell culture system to maintain the VEGFR-3+ endothelial cell (EC) and investigated the role of VEGFR-3 signals at the cellular level. In this system packed clusters of ECs were formed. Whereas addition of exogenous VEGF-A induced EC dispersion, VEGF-C, which can also stimulate VEGFR-2, promoted EC growth without disturbing the EC clusters. Moreover, addition of AFL4, an antagonistic MoAb for VEGFR-3, resulted in EC dispersion. Cytological analysis showed that VEGF-A– and AFL4-treated ECs were indistinguishable in many aspects but were distinct from the cytological profile induced by antagonistic MoAb for VE-cadherin (VECD-1). As AFL4- induced EC dispersion requires VEGF-A stimulation, it is likely that VEGFR-3 signals negatively modulate VEGFR-2. This result provides new insights into the involvement of VEGFR-3 signals in the maintenance of vascular integrity through modulation of VEGFR-2 signals. Moreover, our findings suggest that the mechanisms underlying AFL4-induced EC dispersion are distinct from those underlying VECD-1–induced dispersion for maintenance of EC integrity.

ANGIOGENIC IMBALANCES IN THE PATHOGENESIS OF PREGNANCY COMPLICATIONS

2014 ◽  
Vol 25 (1) ◽  
pp. 42-58
Author(s):  
JIMMY ESPINOZA
Keyword(s):  
Pregnancy Complications ◽  
Angiogenic Factors ◽  
Angiogenic Factor ◽  
Soluble Form ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Maternal Circulation ◽  
Soluble Endoglin ◽  
Endothelial Growth Factor

Endothelial cell proliferation and survival require continuous low levels of vascular endothelial growth factor (VEGF). The bioavailability of this angiogenic factor appears to be regulated by anti-angiogenic factors, including the soluble form of VEGF receptor 1 (sFlt-1) in the non-pregnant and pregnant states. During pregnancy a VEGF antagonist (sFlt-1) and other anti-angiogenic factors, including soluble endoglin (s-Eng), are produced by the human placenta and released into the maternal circulation; an excess of these anti-angiogenic factors can lead into angiogenic imbalances and pregnancy complications. This is important because regulation of VEGF action on angiogenic balances appears to be essential for a successful pregnancy.

scholarly journals Vascular Endothelial Growth Factor Induces Branching Morphogenesis/Tubulogenesis in Renal Epithelial Cells in a Neuropilin-Dependent Fashion

2005 ◽  
Vol 25 (17) ◽  
pp. 7441-7448 ◽  
Author(s):  
Anil Karihaloo ◽  
S. Ananth Karumanchi ◽  
William L. Cantley ◽  
Shivalingappa Venkatesha ◽  
Lloyd G. Cantley ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Epithelial Cells ◽  
Neutralizing Antibodies ◽  
Branching Morphogenesis ◽  
Tube Formation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Renal Epithelial Cell ◽  
Endothelial Growth Factor

ABSTRACT Vascular endothelial growth factor (VEGF) is well characterized for its role in endothelial cell differentiation and vascular tube formation. Alternate splicing of the VEGF gene in mice results in various VEGF-A isoforms, including VEGF-121 and VEGF-165. VEGF-165 is the most abundant isoform in the kidney and has been implicated in glomerulogenesis. However, its role in the tubular epithelium is not known. We demonstrate that VEGF-165 but not VEGF-121 induces single-cell branching morphogenesis and multicellular tubulogenesis in mouse renal tubular epithelial cells and that these morphogenic effects require activation of the phosphatidylinositol 3-kinase (PI 3-K) and, to a lesser degree, the extracellular signal-regulated kinase and protein kinase C signaling pathways. Further, VEGF-165-stimulated sheet migration is dependent only on PI 3-K signaling. These morphogenic effects of VEGF-165 require activation of both VEGF receptor 2 (VEGFR-2) and neuropilin-1 (Nrp-1), since neutralizing antibodies to either of these receptors or the addition of semaphorin 3A (which blocks VEGF-165 binding to Nrp-1) prevents the morphogenic response and the phosphorylation of VEGFR-2 along with the downstream signaling. We thus conclude that in addition to endothelial vasculogenesis, VEGF can induce renal epithelial cell morphogenesis in a Nrp-1-dependent fashion.

Vascular endothelial growth factor promotes cardiomyocyte differentiation of embryonic stem cells

2006 ◽  
Vol 291 (4) ◽  
pp. H1653-H1658 ◽  
Author(s):  
Yu Chen ◽  
Ivo Amende ◽  
Thomas G. Hampton ◽  
Yinke Yang ◽  
Qingen Ke ◽  
...  
Keyword(s):  
Stem Cells ◽  
Vascular Endothelial Growth Factor ◽  
Embryonic Stem Cells ◽  
Growth Factor ◽  
Troponin I ◽  
Embryonic Stem ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Cardiomyocyte Differentiation ◽  
Endothelial Growth Factor

Embryonic stem cells (ESCs) overexpressing the vascular endothelial growth factor (VEGF) improve cardiac function in mouse models of myocardial ischemia and infarction by mechanisms that are poorly understood. Here we studied the effects of VEGF on cardiomyocyte differentiation of mouse ESCs in vitro. We used flow cytometry to determine the expression of α-myosin heavy chain (α-MHC), cardiac troponin I (cTn-I), and Nkx2.5 in differentiated ESCs. VEGF (20 ng/ml) significantly enhanced α-MHC, cTn-I, and Nkx2.5 expression in differentiated ESCs. Western blot analysis confirmed these findings. We found that VEGF receptor FMS-like tyrosine kinase-1 (Flt-1) and fetal liver kinase-1 (Flk-1) expression increased during ESC differentiation. Antibodies against Flk-1 totally blocked and against Flt-1 partially blocked VEGF-induced NKx2.5-positive-stained cells. The ERK inhibitor PD-098059 abolished VEGF-induced cardiomyocyte differentiation of ESCs. Our results suggest that VEGF promotes cardiomyocyte differentiation predominantly by ERK-mediated Flk-1 activation and, to a lesser extent, by Flt-1 activation. These findings may be of significance for stem cell and growth factor therapies to regenerate failing cardiomyocytes.

Vascular endothelial growth factor accelerates compensatory lung growth after unilateral pneumonectomy

2007 ◽  
Vol 292 (3) ◽  
pp. L742-L747 ◽  
Author(s):  
Maromi K. Sakurai ◽  
Sang Lee ◽  
Danielle A. Arsenault ◽  
Vania Nose ◽  
Jay M. Wilson ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Growth Factor ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Lung Growth ◽  
Compensatory Lung Growth ◽  
Chemical Inhibitors ◽  
Proliferation And Apoptosis ◽  
Endothelial Growth Factor

We hypothesize that compensatory lung growth after unilateral pneumonectomy in a murine model is, in part, angiogenesis dependent and can be altered using angiogenic agents, possibly through regulation of endothelial cell proliferation and apoptosis. Left pneumonectomy was performed in mice. Mice were then treated with proangiogenic factors [vascular endothelial growth factor (VEGF); basic fibroblast growth factor (bFGF)], VEGF receptor antibodies (MF-1, DC101), and VEGF receptor small molecule chemical inhibitors. Lung volume and mass were measured. The lungs were analyzed using immunohistochemistry by CD31 staining, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling, type II pneumocytes staining, and proliferating cell nuclear antigen. Compensatory lung growth was complete by postoperative day 10 and was associated with diffuse apoptosis of endothelial cells and pneumocytes. This process was accelerated by VEGF, such that growth was complete by postoperative day 4 with similar associated apoptosis. bFGF had no effect on lung growth. MF-1 and DC101 had no effect. The VEGF receptor small molecule chemical inhibitors also had no effect. VEGF, but not bFGF, accelerates growth. VEGF receptor inhibitors do not block growth, suggesting that other proangiogenic factors play a role or can compensate for VEGF receptor blockade. Diffuse apoptosis, endothelial cell and pneumocyte, occurs at cessation of both normal compensatory and VEGF-accelerated growth. Angiogenesis modulators may control growth via regulation of endothelial cell proliferation and apoptosis, although the exact relationship between endothelial cells and pneumocytes has yet to be determined. The fact that bFGF did not accelerate growth in our model when it did accelerate regeneration in the liver model suggests that angiogenesis during organ regeneration is regulated in an organ-specific manner.

scholarly journals Spreds Are Essential for Embryonic Lymphangiogenesis by Regulating Vascular Endothelial Growth Factor Receptor 3 Signaling

2007 ◽  
Vol 27 (12) ◽  
pp. 4541-4550 ◽  
Author(s):  
Koji Taniguchi ◽  
Ri-ichiro Kohno ◽  
Toranoshin Ayada ◽  
Reiko Kato ◽  
Kenji Ichiyama ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Blood Vessels ◽  
Lymphatic Vessels ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Erk Activation ◽  
Factor C ◽  
Endothelial Growth Factor

ABSTRACT Spred/Sprouty family proteins negatively regulate growth factor-induced ERK activation. Although the individual physiological roles of Spred-1 and Spred-2 have been investigated using gene-disrupted mice, the overlapping functions of Spred-1 and Spred-2 have not been clarified. Here, we demonstrate that the deletion of both Spred-1 and Spred-2 resulted in embryonic lethality at embryonic days 12.5 to 15.5 with marked subcutaneous hemorrhage, edema, and dilated lymphatic vessels filled with erythrocytes. This phenotype resembled that of Syk −/− and SLP-76 −/− mice with defects in the separation of lymphatic vessels from blood vessels. The number of LYVE-1-positive lymphatic vessels and lymphatic endothelial cells increased markedly in Spred-1/2-deficient embryos compared with WT embryos, while the number of blood vessels was not different. Ex vivo colony assay revealed that Spred-1/2 suppressed lymphatic endothelial cell proliferation and/or differentiation. In cultured cells, the overexpression of Spred-1 or Spred-2 strongly suppressed vascular endothelial growth factor-C (VEGF-C)/VEGF receptor (VEGFR)-3-mediated ERK activation, while Spred-1/2-deficient cells were extremely sensitive to VEGFR-3 signaling. These data suggest that Spreds play an important role in lymphatic vessel development by negatively regulating VEGF-C/VEGFR-3 signaling.

scholarly journals Correlation of endothelial cell proliferation with vascular endothelial growth factor in endometrium of women with menorrhagia

2017 ◽  
Vol 5 (5) ◽  
pp. 2034
Author(s):  
Kiran B. Mehra ◽  
Nitin M. Gangane ◽  
Deepti R. Joshi
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Cell Proliferation ◽  
Endothelial Cell Proliferation ◽  
P Value ◽  
Vascular Endothelial ◽  
Luminal Surface ◽  
Vegf Expression ◽  
Secretory Phase ◽  
Endothelial Proliferation ◽  
Endothelial Growth Factor

Background: Approximately 30% of women of reproductive age experience excessive blood loss during menstruation. In 50% of cases, menorrhagia has no underlying pathology. However, until recently, the only permanent cure for menorrhagia was hysterectomy. In this study we aim to determine the correlation of vascular endothelial growth factor (VEGF) expression with markers of endometrial endothelial cell proliferation like proliferating cell nuclear antigen (PCNA) and Cluster Determination (CD34).Methods: A total of 100 patients with history of menorrhagia were selected for study. Double Immunohistochemistry was performed on these endometrial biopsy sections. Proliferating endothelial cells were identified by an immunohistochemical double staining technique with PCNA and CD34. VEGF expression was also seen in endometrial biopsy.Results: In general, expression of both VEGF and PCNA was more in functional layer than basal layer in both menorrhagic patients as well as non menorrhagic patients.  When glandular cytoplasmic VEGF expression was compared with PCNA the association was statistically significant whereas completely opposite findings was seen with glandular luminal surface VEGF positivity but the association was statistically significant. In secretory phase (p-value<0.001) there was highly statistically significant association in PCNA grading with glandular luminal surface VEGF positivity whereas when we correlated PCNA with  cytoplasmic  glandular VEGF in secretory phase it was statistically significant (p-value<0.001).Conclusions: The endothelial proliferation was significantly higher in menorrhagia patients during late secretory phase of cycle than controls. We were able to demonstrate increased endothelial proliferation in patients in the premenstrual part of cycle.

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