scholarly journals Endothelial Ca2+ oscillations reflect VEGFR signaling-regulated angiogenic capacity in vivo

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Yasuhiro Yokota ◽  
Hiroyuki Nakajima ◽  
Yuki Wakayama ◽  
Akira Muto ◽  
Koichi Kawakami ◽  
...  
Keyword(s):  
Stalk Cell ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Cardinal Vein ◽  
Sprouting Angiogenesis ◽  
Spatio Temporal ◽  
Endothelial Growth Factor ◽  
Tip Cells ◽  
Selection Of

Sprouting angiogenesis is a well-coordinated process controlled by multiple extracellular inputs, including vascular endothelial growth factor (VEGF). However, little is known about when and how individual endothelial cell (EC) responds to angiogenic inputs in vivo. Here, we visualized endothelial Ca2+ dynamics in zebrafish and found that intracellular Ca2+ oscillations occurred in ECs exhibiting angiogenic behavior. Ca2+ oscillations depended upon VEGF receptor-2 (Vegfr2) and Vegfr3 in ECs budding from the dorsal aorta (DA) and posterior cardinal vein, respectively. Thus, visualizing Ca2+ oscillations allowed us to monitor EC responses to angiogenic cues. Vegfr-dependent Ca2+ oscillations occurred in migrating tip cells as well as stalk cells budding from the DA. We investigated how Dll4/Notch signaling regulates endothelial Ca2+ oscillations and found that it was required for the selection of single stalk cell as well as tip cell. Thus, we captured spatio-temporal Ca2+ dynamics during sprouting angiogenesis, as a result of cellular responses to angiogenic inputs.

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.

Carbon monoxide inhibits sprouting angiogenesis and vascular endothelial growth factor receptor-2 phosphorylation

2015 ◽  
Vol 113 (02) ◽  
pp. 329-337 ◽  
Author(s):  
Peter W. Hewett ◽  
Takeshi Fujisawa ◽  
Samir Sissaoui ◽  
Meng Cai ◽  
Geraldine Gueron ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Carbon Monoxide ◽  
Growth Factor ◽  
Umbilical Vein ◽  
Growth Factor Receptor ◽  
Tube Formation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Sprouting Angiogenesis ◽  
Endothelial Growth Factor

SummaryCarbon monoxide (CO) is a gaseous autacoid known to positively regulate vascular tone; however, its role in angiogenesis is unknown. The aim of this study was to investigate the effect of CO on angiogenesis and vascular endothelial growth factor (VEGF) receptor-2 phosphorylation. Human umbilical vein endothelial cells (HUVECs) were cultured on growth factor-reduced Matrigel and treated with a CO-releasing molecule (CORM-2) or exposed to CO gas (250 ppm). Here, we report the surprising finding that exposure to CO inhibits vascular endothelial growth factor (VEGF)-induced endothelial cell actin reorganisation, cell proliferation, migration and capillary-like tube formation. Similarly, CO suppressed VEGF-mediated phosphorylation of VEGFR-2 at tyrosine residue 1175 and 1214 and basic fibroblast growth factor- (FGF-2) and VEGF-mediated Akt phosphorylation. Consistent with these data, mice exposed to 250 ppm CO (1h/day for 14 days) exhibited a marked decrease in FGF-2-induced Matrigel plug angiogenesis (p<0.05). These data establish a new biological function for CO in angiogenesis and point to a potential therapeutic use for CO as an anti-angiogenic agent in tumour suppression.

scholarly journals Oral Delivery of a Tetrameric Tripeptide Inhibitor of VEGFR1 Suppresses Pathological Choroid Neovascularization

2020 ◽  
Vol 21 (2) ◽  
pp. 410 ◽  
Author(s):  
Valeria Tarallo ◽  
Emanuela Iaccarino ◽  
Valeria Cicatiello ◽  
Riccardo Sanna ◽  
Menotti Ruvo ◽  
...  
Keyword(s):  
Intravitreal Injection ◽  
Oral Delivery ◽  
Age Related Macular Degeneration ◽  
Preclinical Model ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Systemic Delivery ◽  
Age Related ◽  
Endothelial Growth Factor

Age-related macular degeneration (AMD) is the primary cause of blindness in advanced countries. Repeated intravitreal delivery of anti-vascular endothelial growth factor (VEGF) agents has represented an important advancement for the therapy of wet AMD with significative results in terms of blindness prevention and partial vision restore. Nonetheless, some patients are not responsive or do not attain significant visual improvement, intravitreal injection may cause serious complications and important side effects have been reported for the prolonged block of VEGF-A. In order to evaluate new anti-angiogenic strategies, we focused our attention on VEGF receptor 1 (VEGFR1) developing a specific VEGFR-1 antagonist, a tetrameric tripeptide named inhibitor of VEGFR 1 (iVR1). We have evaluated its anti-angiogenic activity in the preclinical model of AMD, the laser-induced choroid neovascularization (CNV). iVR1 is able to potently inhibit CNV when delivered by intravitreal injection. Surprisingly, it is able to significantly reduce CNV also when delivered by gavage. Our data show that the specific block of VEGFR1 in vivo represents a valid alternative to the block of VEGF-A and that the inhibition of the pathological neovascularization at ocular level is also possible by systemic delivery of compounds not targeting VEGF-A.

scholarly journals Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF

Blood ◽  
2007 ◽  
Vol 110 (2) ◽  
pp. 624-631 ◽  
Author(s):  
Yuhui Huang ◽  
Xiaolan Chen ◽  
Mikhail M. Dikov ◽  
Sergey V. Novitskiy ◽  
Claudio A. Mosse ◽  
...  
Keyword(s):  
Cell Function ◽  
Critical Role ◽  
T Cell Development ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Host Interactions ◽  
Selective Blockade ◽  
Independent Effects ◽  
Endothelial Growth Factor

Abstract Vascular endothelial growth factor (VEGF), a major factor in tumor-host interactions, plays a critical role in the aberrant hematopoiesis observed in cancer-bearing hosts. To dissect the roles of VEGF receptor (VEGFR)-1 and VEGFR-2 in cancer-associated hematopoiesis in vivo, we selectively stimulated VEGFR-1 and VEGFR-2 by continuous infusion of receptor-specific ligands or selective blockade with VEGF receptor-specific antibodies in mice infused with recombinant VEGF at levels observed in tumor-bearing animals. We found that the effect of VEGF on the accumulation of Gr1+CD11b+ cells is mediated by VEGFR-2, but that the 2 receptors have opposite effects on lymphocyte development. Pathophysiologic levels of VEGF strongly inhibit T-cell development via VEGFR-2, whereas VEGFR-1 signaling decreases this inhibition. VEGFR-1, and not VEGFR-2, signaling is responsible for the observed increase of splenic B cells. Both receptors are capable of inhibiting dendritic cell function. These data suggest that most of observed aberrant hematopoiesis caused by excess tumor-derived VEGF is mediated by VEGFR-2, and VEGFR-1 alone has very limited independent effects but clearly both positively and negatively modulates the effects of VEGFR-2. Our findings suggest that selective blockade of VEGFR-2 rather than of both receptors may optimally overcome the adverse hematologic consequences of elevated VEGF levels found in malignancy.

VEGF promotes vascular sympathetic innervation

2008 ◽  
Vol 294 (6) ◽  
pp. H2646-H2652 ◽  
Author(s):  
Stephen B. Marko ◽  
Deborah H. Damon
Keyword(s):  
Blood Vessels ◽  
Sympathetic Innervation ◽  
Nerve Fibers ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Sympathetic Nerve Fibers ◽  
Endothelial Growth Factor ◽  
Immunohistochemical Analyses

The sympathetic nervous system, via postganglionic innervation of blood vessels and the heart, is an important determinant of cardiovascular function. The mechanisms underlying sympathetic innervation of targets are not fully understood. This study tests the hypothesis that target-derived vascular endothelial growth factor (VEGF) promotes sympathetic innervation of blood vessels. Western blot and immunohistochemical analyses indicate that VEGF is produced by vascular cells in arteries and that VEGF receptors are expressed on sympathetic nerve fibers innervating arteries. In vitro, exogenously added VEGF and VEGF produced by vascular smooth muscle cells (VSMCs) in sympathetic neurovascular cocultures inhibited semaphorin 3A (Sema3A)-induced collapse of sympathetic growth cones. In the absence of Sema3A, VEGF and VSMCs also increased growth cone area. These effects were mediated via VEGF receptor 1. In vivo, the neutralization of VEGF inhibited the reinnervation of denervated femoral arteries. These data demonstrate that target-derived VEGF plays a previously unrecognized role in promoting the growth of sympathetic axons.

A vascular endothelial growth factor 121 (VEGF121)-based dual PET/optical probe for in vivo imaging of VEGF receptor expression

Biomaterials ◽  
2013 ◽  
Vol 34 (28) ◽  
pp. 6839-6845 ◽  
Author(s):  
Choong Mo Kang ◽  
Hyun-Jung Koo ◽  
Kyo Chul Lee ◽  
Yearn Seong Choe ◽  
Joon Young Choi ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
In Vivo Imaging ◽  
Optical Probe ◽  
Receptor Expression ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model of angiogenesis

1996 ◽  
Vol 270 (5) ◽  
pp. H1803-H1811 ◽  
Author(s):  
J. Li ◽  
L. F. Brown ◽  
M. G. Hibberd ◽  
J. D. Grossman ◽  
J. P. Morgan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Growth Factor ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Infarct Zone ◽  
Receptor System ◽  
Cell Mitogen ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen that is thought to function by interacting with two high-affinity receptors, flk-1 and flt-1. In an adult heart, angiogenesis can occur in a number of pathological conditions, including atherosclerosis, hypertrophy, and infarction. To determine the role played by VEGF, flk-1, and flt-1 in this process in vivo, we studied the expression of the growth factor and its receptors in a rat infarct model. After an acute myocardial infarction, we observed an initial rapid (1h) rise in VEGF (275%), flk-1 (375%), and flt-1 (400%) mRNA expression throughout the entire heart. Initial diffuse induction of VEGF, flk-1, and flt-1 expression in the left ventricle was later replaced by an increase predominantly limited to perimyocardial infarction area where angiogenesis was taking place. In situ hybridization showed at 6 h after infarction, viable myocytes adjacent to the infarct zone expressed markedly increased amounts of VEGF. At both 6 and 24 h, microvessels at the infarct edge overexpressed both flk-1 and flt-1 mRNAs; at 3 and 7 days new vessels infiltrating the infarct also overexpressed both receptors and continued for as late as 6 wk. In summary, acute myocardial infarction is accompanied by rapid and prolonged increase in expression of VEGF and its receptors with characteristic spatial and temporal kinetic. These findings suggest that the VEGF/VEGF receptor system plays an important role in the angiogenesis and stromal deposition associated with myocardial infarction.

scholarly journals Inhibition of the Vascular Endothelial Cell (VE)-Specific Adhesion Molecule VE-Cadherin Blocks Gonadotropin-Dependent Folliculogenesis and Corpus Luteum Formation and Angiogenesis

Endocrinology ◽  
2005 ◽  
Vol 146 (3) ◽  
pp. 1053-1059 ◽  
Author(s):  
Gary S. Nakhuda ◽  
Ralf C. Zimmermann ◽  
Peter Bohlen ◽  
Fang Liao ◽  
Mark V. Sauer ◽  
...  
Keyword(s):  
Corpus Luteum ◽  
Adhesion Molecule ◽  
Vascular Endothelial Cell ◽  
In Vitro Assays ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
The Many ◽  
Endothelial Growth Factor

Although it has been previously demonstrated that administration of anti-vascular endothelial growth factor (VEGF) receptor-2 antibodies to hypophysectomized (Hx) mice during gonadotropin-stimulated folliculogenesis and luteogenesis inhibits angiogenesis in the developing follicle and corpus luteum (CL), it is unclear which of the many components of VEGF inhibition are important for the inhibitory effects on ovarian angiogenesis. To examine whether ovarian angiogenesis can be more specifically targeted, we administered an antibody to VE-cadherin (VE-C), an interendothelial adhesion molecule, to Hx mice during gonadotropin stimulation. In tumor models and in vivo and in vitro assays, the anti-VE-C antibody E4G10 has been shown to specifically inhibit angiogenesis, but VE-C has yet to be inhibited in the context of ovarian angiogenesis. In addition to studying the effect on neovascularization in the follicular and luteal phases, we also examined the effect of E4G10 on established vessels of the CL of pregnancy. The results demonstrate that E4G10 specifically blocks neovascularization in the follicular and luteal phases, causing an inhibition of preovulatory follicle and CL development, a decrease in the vascular area, and an inhibition of function demonstrated by reduced hormone levels. However, when administered during pregnancy, unlike anti-VEGF receptor-2 antibody, E4G10 is unable to cause disruption of the established vessels of the mature CL. These data demonstrate that E4G10 causes a specific inhibition of neovascularization in the ovary without destabilizing preexisting vasculature.

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