scholarly journals Cardiovascular ephrinB2 function is essential for embryonic angiogenesis

Development ◽  
2002 ◽  
Vol 129 (6) ◽  
pp. 1397-1410 ◽  
Author(s):  
Sebastian S. Gerety ◽  
David J. Anderson
Keyword(s):  
Endothelial Cells ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Vascular Endothelial Cells ◽  
Mesenchymal Cells ◽  
Vascular Endothelial ◽  
Vascular Cells ◽  
Ephb Receptor ◽  
Essential Function ◽  
Specific Deletion

EphrinB2, a transmembrane ligand of EphB receptor tyrosine kinases, is specifically expressed in arteries. In ephrinB2 mutant embryos, there is a complete arrest of angiogenesis. However, ephrinB2 expression is not restricted to vascular endothelial cells, and it has been proposed that its essential function may be exerted in adjacent mesenchymal cells. We have generated mice in which ephrinB2 is specifically deleted in the endothelium and endocardium of the developing vasculature and heart. We find that such a vascular-specific deletion of ephrinB2 results in angiogenic remodeling defects identical to those seen in the conventional ephrinB2 mutants. These data indicate that ephrinB2 is required specifically in endothelial and endocardial cells for angiogenesis, and that ephrinB2 expression in perivascular mesenchyme is not sufficient to compensate for the loss of ephrinB2 in these vascular cells.

scholarly journals Regulation of vasculogenesis and angiogenesis by EphB/ephrin-B2 signaling between endothelial cells and surrounding mesenchymal cells

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1326-1333 ◽  
Author(s):  
Yuichi Oike ◽  
Yasuhiro Ito ◽  
Koichi Hamada ◽  
Xiu-Qin Zhang ◽  
Keishi Miyata ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Receptor Tyrosine Kinases ◽  
Vascular Endothelial Cells ◽  
Mesenchymal Cells ◽  
Ephb Receptor ◽  
Vasculogenesis And Angiogenesis

Although the cellular and molecular mechanisms governing angiogenesis are only beginning to be understood, signaling through endothelial-restricted receptors, particularly receptor tyrosine kinases, has been shown to play a pivotal role in these events. Recent reports show that EphB receptor tyrosine kinases and their transmembrane-type ephrin-B2 ligands play essential roles in the embryonic vasculature. These studies suggest that cell-to-cell repellent effects due to bidirectional EphB/ephrin-B2 signaling may be crucial for vascular development, similar to the mechanism described for neuronal development. To test this hypothesis, we disrupted the precise expression pattern of EphB/ephrin-B2 in vivo by generating transgenic (CAGp-ephrin-B2 Tg) mice that express ephrin-B2 under the control of a ubiquitous and constitutive promoter, CMV enhancer-β-actin promoter-β-globin splicing acceptor (CAG). These mice displayed an abnormal segmental arrangement of intersomitic vessels, while such anomalies were not observed in Tie-2p-ephrin-B2 Tg mice in which ephrin-B2 was overexpressed in only vascular endothelial cells (ECs). This finding suggests that non-ECs expressing ephrin-B2 alter the migration of ECs expressing EphB receptors into the intersomitic region where ephrin-B2 expression is normally absent. CAGp-ephrin-B2 Tg mice show sudden death at neonatal stages from aortic dissecting aneurysms due to defective recruitment of vascular smooth muscle cells to the ascending aorta. EphB/ephrin-B2 signaling between endothelial cells and surrounding mesenchymal cells plays an essential role in vasculogenesis, angiogenesis, and vessel maturation.

scholarly journals The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells.

1993 ◽  
Vol 178 (6) ◽  
pp. 2077-2088 ◽  
Author(s):  
A Kaipainen ◽  
J Korhonen ◽  
K Pajusola ◽  
O Aprelikova ◽  
M G Persico ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Vascular Endothelial Cells ◽  
Expression Patterns ◽  
Vascular Endothelial ◽  
Vascular Permeability Factor ◽  
Kinase Gene ◽  
Permeability Factor

The growth factor receptors expressed on endothelial cells are of special interest because of their potential to program endothelial cell growth and differentiation during development and neovascularization in various pathological states, such as wound healing and angiogenesis associated with tumorigenesis. Vascular endothelial growth factor ([VEGF] also known as vascular permeability factor) is a potent mitogen and permeability factor, which has been suggested to play a role in embryonic and tumor angiogenesis. The newly cloned FLT4 receptor tyrosine kinase gene encodes a protein related to the VEGF receptors FLT1 and KDR/FLK-1. We have here studied the expression of FLT4 and the other two members of this receptor family in human fetal tissues by Northern and in situ hybridization. These results were also compared with the sites of expression of VEGF and the related placenta growth factor (PlGF). Our results reveal FLT4 mRNA expression in vascular endothelial cells in developing vessels of several organs. A comparison of FLT4, FLT1 and KDR/FLK-1 receptor mRNA signals shows overlapping, but distinct expression patterns in the tissues studied. Certain endothelia lack one or two of the three receptor mRNAs. These data suggest that the receptor tyrosine kinases encoded by the FLT gene family may have distinct functions in the regulation of the growth/differentiation of blood vessels.

scholarly journals Axl Is Essential for in-vitro Angiogenesis Induced by Vitreous From Patients With Proliferative Diabetic Retinopathy

2021 ◽  
Vol 8 ◽  
Author(s):  
Wenyi Wu ◽  
Huizuo Xu ◽  
Zhishang Meng ◽  
Jianxi Zhu ◽  
Siqi Xiong ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Diabetic Retinopathy ◽  
Proliferative Diabetic Retinopathy ◽  
Tyrosine Kinases ◽  
Vascular Endothelial Cells ◽  
Specific Inhibitor ◽  
Cell Types ◽  
Specific Protein ◽  
Vascular Endothelial

Proliferative diabetic retinopathy (PDR), characterized mainly with abnormal epiretinal angiogenesis forming fibrovascular membranes (FVMs), threatens vision of people with diabetes; FVMs consist of extracellular matrix and a variety of cell types including vascular endothelial cells. Axl, one of receptor tyrosine kinases, can be activated indirectly by vascular endothelial growth factor-A (VEGF-A) via an intracellular route for promoting angiogenesis. In this study, we revealed that growth arrest-specific protein 6 (Gas6), a specific ligand of Axl, was elevated in vitreous from patients with PDR and that Axl was activated in FVMs from patients with PDR. In addition, we demonstrated that in cultured human retinal microvascular endothelial cells (HRECs), Axl inhibition via suppression of Axl expression with Clustered Regularly Interspaced Short Palindromic Repeats/ CRISPR-associated protein 9 or through inactivation with its specific inhibitor R428 blocked PDR vitreous-induced Akt activation and proliferation of HRECs. Furthermore, PDR vitreous-heightened migration and tube formation of HRECs were also blunted by restraining Axl. These results indicate that in the pathogenesis of PDR, Axl can be activated by Gas6 binding directly and by VEGF-A via an intracellular route indirectly, suggesting that Axl plays a pivotal role in the development of PDR and that Axl inhibition shows a bright promise for PDR therapy.

scholarly journals Toxicities of and inflammatory responses to moxifloxacin, cefuroxime, and vancomycin on retinal vascular cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hitomi Miyake ◽  
Dai Miyazaki ◽  
Yumiko Shimizu ◽  
Shin-ichi Sasaki ◽  
Takashi Baba ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Viability ◽  
Esterase Activity ◽  
Vascular Endothelial Cells ◽  
Membrane Damage ◽  
Retinal Vasculitis ◽  
Retinal Toxicity ◽  
Diaminopimelic Acid ◽  
Vascular Endothelial ◽  
Vascular Cells

Abstract Prophylactic intracameral injection of antibiotics is commonly used to prevent endophthalmitis after cataract surgery. However, devastating visual complications have been reported including hemorrhagic occlusive retinal vasculitis (HORV).To determine the toxic and inflammatory effects of moxifloxacin, cefuroxime, and vancomycin on human retinal vascular cells, human retinal vascular endothelial cells (RVEC) and pericytes were exposed to three antibiotics, and the adverse effects were assessed by membrane damage, loss of intrinsic esterase activity, kinetic cell viability, and inflammatory cytokine secretion. Their retinal toxicity was examined by live/dead assays after an intravitreal injection of the three antibiotics into mice eyes. In vascular cells in culture, membrane damage and loss of esterase activity were induced after exposure to the three antibiotics. The toxic effects were most obvious after moxifloxacin (RVEC, ≥125 μg/mL; pericytes, ≥1000 μg/mL) at 24 h. Cefuroxime also reduced esterase activity and the membrane integrity of vascular cells but were less toxic than moxifloxacin. Kinetic cell viability testing showed that 500 μg/mL of moxifloxacin exposure induced significant decrease (29%) in the viability as early as 1 h. When the inflammatory effects of the antibiotics were examined, a significant induction of IL-8 was observed especially by RVECs after exposure to cefuroxime or vancomycin which was exacerbated by L-alanyl-γ-D-glutamyl-meso-diaminopimelic acid (Tri-DAP), a NOD1 ligand. Intravitreal injections in mice showed that cefuroxime and vancomycin caused retinal and vascular toxicity extending to the inner nuclear layers. Collectively, moxifloxacin causes immediate damage to retinal vascular cells in vitro, while cefuroxime and vancomycin induced significant inflammatory effects on vascular endothelial cells and caused retinal toxicity. Surgeons need to be cautious of the toxicity when antibiotics are used prophylactically especially by intravitreal administration.

scholarly journals The vascular endothelial cell-expressed prion protein doppel promotes angiogenesis and blood-brain barrier development

Development ◽  
2020 ◽  
Vol 147 (18) ◽  
pp. dev193094
Author(s):  
Zhihua Chen ◽  
John E. Morales ◽  
Naze Avci ◽  
Paola A. Guerrero ◽  
Ganesh Rao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Blood Vessel ◽  
Prion Protein ◽  
Tyrosine Kinases ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial Cell ◽  
Vascular Endothelial ◽  
And Migration ◽  
Migration Analysis

ABSTRACTThe central nervous system (CNS) contains a complex network of blood vessels that promote normal tissue development and physiology. Abnormal control of blood vessel morphogenesis and maturation is linked to the pathogenesis of various neurodevelopmental diseases. The CNS-specific genes that regulate blood vessel morphogenesis in development and disease remain largely unknown. Here, we have characterized functions for the gene encoding prion protein 2 (Prnd) in CNS blood vessel development and physiology. Prnd encodes the glycosylphosphatidylinositol (GPI)-linked protein doppel, which is expressed on the surface of angiogenic vascular endothelial cells, but is absent in quiescent endothelial cells of the adult CNS. During CNS vascular development, doppel interacts with receptor tyrosine kinases and activates cytoplasmic signaling pathways involved in endothelial cell survival, metabolism and migration. Analysis of mice genetically null for Prnd revealed impaired CNS blood vessel morphogenesis and associated endothelial cell sprouting defects. Prnd−/− mice also displayed defects in endothelial barrier integrity. Collectively, these data reveal novel mechanisms underlying doppel control of angiogenesis in the developing CNS, and may provide new insights about dysfunctional pathways that cause vascular-related CNS disorders.

VEGF regulates the mobilization of VEGFR2/KDR from an intracellular endothelial storage compartment

Blood ◽  
2006 ◽  
Vol 108 (8) ◽  
pp. 2624-2631 ◽  
Author(s):  
Alexandra Gampel ◽  
Lara Moss ◽  
Matt C. Jones ◽  
Val Brunton ◽  
Jim C. Norman ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Tyrosine Kinases ◽  
Intracellular Trafficking ◽  
Receptor Tyrosine Kinases ◽  
Significant Proportion ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Src Tyrosine Kinase ◽  
Endothelial Growth Factor

AbstractEndothelial cells respond to vascular endothelial growth factor (VEGF) to produce new blood vessels. This process of angiogenesis makes a critical contribution during embryogenesis and also in the response to ischemia in adult tissues. We have studied the intracellular trafficking of the major VEGF receptor KDR (VEGFR2). Unlike other related growth factor receptors, we find that a significant proportion of KDR is held in an endosomal storage pool within endothelial cells. We find that KDR can be delivered to the plasma membrane from this intracellular pool and that VEGF stimulates this recycling to the cell surface. KDR recycling appears to be distinct from the previously characterized Rab4- and Rab11-dependent pathways, but, instead, KDR+ recycling vesicles contain Src tyrosine kinase and VEGF-stimulated recycling requires Src activation. Taken together, these data show that intracellular trafficking of KDR is markedly different from other receptor tyrosine kinases and suggest that the regulation of KDR trafficking by VEGF provides a novel mechanism for controlling the sensitivity of endothelial cells to proangiogenic signals.

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