VEGF-A/VEGFR2 signaling network in endothelial cells relevant to angiogenesis

Islet vascularization is essential for intact islet function and glucose homeostasis. We have previously shown that primary cilia directly regulate insulin secretion. However, it remains unclear whether they are also implicated in islet vascularization. At eight weeks, murine Bbs4-/-islets show significantly lower intra-islet capillary density with enlarged diameters. Transplanted Bbs4-/- islets exhibit delayed re-vascularization and reduced vascular fenestration after engraftment, partially impairing vascular permeability and glucose delivery to β-cells. We identified primary cilia on endothelial cells as the underlying cause of this regulation, via the vascular endothelial growth factor-A (VEGF-A)/VEGF receptor 2 (VEGFR2) pathway. In vitro silencing of ciliary genes in endothelial cells disrupts VEGF-A/VEGFR2 internalization and downstream signaling. Consequently, key features of angiogenesis including proliferation and migration are attenuated in human BBS4 silenced endothelial cells. We conclude that endothelial cell primary cilia regulate islet vascularization and vascular barrier function via the VEGF-A/VEGFR2 signaling pathway.

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Thioredoxin-Interacting Protein Mediates Sustained VEGFR2 Signaling in Endothelial Cells Required for Angiogenesis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.112.300386 ◽

2013 ◽

Vol 33 (4) ◽

pp. 737-743 ◽

Cited By ~ 24

Author(s):

Shin-Young Park ◽

Xi Shi ◽

Jinjiang Pang ◽

Chen Yan ◽

Bradford C. Berk

Keyword(s):

Endothelial Cells ◽

Interacting Protein ◽

Thioredoxin Interacting Protein ◽

Vegfr2 Signaling

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Feixian Recipe inhibits pulmonary fibrosis by targeting pulmonary microvascular endothelial cells and VEGF/VEGFR2 signaling pathway

Traditional Medicine and Modern Medicine ◽

10.1142/s2575900018500052 ◽

2018 ◽

Vol 01 (01) ◽

pp. 59-67

Author(s):

Lihong Meng ◽

Chen Wang ◽

Zijuan Wang ◽

Ting Yin ◽

Zhe Liu ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Pulmonary Fibrosis ◽

Signal Pathway ◽

Microvascular Endothelial Cells ◽

Vascular Endothelial ◽

Model Group ◽

Vegfr2 Signaling ◽

Adhesion Rate ◽

Endothelial Growth Factor

Objective: To investigate the regulatory mechanism of PMVECs and vascular endothelial growth factor VEGF/vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathway in pulmonary fibrosis and the inhibitory effect of Feixian Recipe (FXR) in pulmonary fibrosis by targeting VEGF/VEGFR2 signal pathway. Methods: In this study, pulmonary microvascular endothelial cells (PMVECs) were successfully isolated from rats with pulmonary fibrosis. Cells were divided into six groups: model group, prednisone group, losartan group and three different concentrated (100[Formula: see text]ug/mL, 60[Formula: see text]ug/mL, 20[Formula: see text]ug/mL) FXR groups. The adhesion rate, migration and closed blood vessels of each PMVECs group were detected. The mRNA expression of VEGF, VEGFR2, phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinases 38 (P38 MAPK) and activin receptor-like kinase (ALK) were detected by SYBR Green I real-time fluorescence quantitative PCR. Results: Compared with the model group, the adhesion rate, migration and angiogenesis of PMVECs were decreased in FXR groups ([Formula: see text]). Compared with prednisone and losartan groups, the mRNA expressions of VEGF, VEGFR2, PI3K and P38 MAPK were down-regulated significantly by FXR ([Formula: see text]). Conclution: FXR can inhibit the migration, adhesion and angiogenesis of PMVECs in rats with pulmonary fibrosis by targeting VEGF/VEGFR2 signal pathway, and inhibit the progress of pulmonary fibrosis.

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Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells

Human Molecular Genetics ◽

10.1093/hmg/ddl108 ◽

2006 ◽

Vol 15 (11) ◽

pp. 1858-1869 ◽

Cited By ~ 36

Author(s):

Amy M. Munchhof ◽

Fang Li ◽

Hilary A. White ◽

Laura E. Mead ◽

Theresa R. Krier ◽

...

Keyword(s):

Endothelial Cells ◽

Growth Factors ◽

Signaling Network

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Mitochondrial UQCRB regulates VEGFR2 signaling in endothelial cells

Journal of Molecular Medicine ◽

10.1007/s00109-013-1049-6 ◽

2013 ◽

Vol 91 (9) ◽

pp. 1117-1128 ◽

Cited By ~ 18

Author(s):

Hye Jin Jung ◽

Yonghyo Kim ◽

Junghwa Chang ◽

Sang Won Kang ◽

Jeong Hun Kim ◽

...

Keyword(s):

Endothelial Cells ◽

Vegfr2 Signaling

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Roles of vascular endothelial growth factor receptor 3 signaling in differentiation of mouse embryonic stem cell–derived vascular progenitor cells into endothelial cells

Blood ◽

10.1182/blood-2004-07-2547 ◽

2005 ◽

Vol 105 (6) ◽

pp. 2372-2379 ◽

Cited By ~ 34

Author(s):

Hiroyuki Suzuki ◽

Tetsuro Watabe ◽

Mitsuyasu Kato ◽

Keiji Miyazawa ◽

Kohei Miyazono

Keyword(s):

Endothelial Cells ◽

Progenitor Cells ◽

Es Cells ◽

Embryonic Stem ◽

Growth Factor Receptor ◽

Endothelial Differentiation ◽

Mouse Es Cells ◽

Vascular Progenitor Cells ◽

Vegfr2 Signaling ◽

Endothelial Growth Factor

AbstractVascular endothelial growth factor receptor 2 (VEGFR2/Flk-1)–positive cells derived from embryonic stem (ES) cells serve as vascular progenitors, which differentiate into endothelial cells (ECs) in the presence of VEGF-A. VEGFR3/Flt-4 (fms-like tyrosine kinase 4) signaling is known to be important for the development of lymphatic endothelial cells (LECs). To elucidate the roles of VEGFR3 signaling in the differentiation of vascular progenitor cells into ECs, we introduced various types of VEGFR3 cDNAs into mouse ES cells. VEGF-C, a ligand for VEGFR2 and VEGFR3, stimulated the endothelial differentiation of the VEGFR2+ cells transfected with the VEGFR3 cDNA but not those transfected with kinasenegative mutants of VEGFR3. The VEGFR3-transfected ECs exhibited high expression levels of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), one of the markers of LECs, and showed efficient binding of hyaluronan. VEGF-C(C152S), which is able to activate VEGFR3 but not VEGFR2, failed to induce the endothelial differentiation of mock- and VEGFR3-transfected VEGFR2+ cells, suggesting the essential role of VEGFR2 signaling for endothelial differentiation. Furthermore, kinase-negative mutants of VEGFR3 prevented the VEGF-C–mediated endothelial differentiation of the vascular progenitor cells. Thus, VEGFR2 signaling is required for the endothelial differentiation of mouse ES cells induced by VEGF-C, and VEGFR3 signaling may confer lymphatic endothelial-like phenotypes to ECs.

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The P-type ATPase transporter ATP7A promotes angiogenesis by limiting autophagic degradation of VEGFR2

Nature Communications ◽

10.1038/s41467-021-23408-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Dipankar Ash ◽

Varadarajan Sudhahar ◽

Seock-Won Youn ◽

Mustafa Nazir Okur ◽

Archita Das ◽

...

Keyword(s):

Endothelial Cells ◽

Autophagy Flux ◽

Potential Therapeutic Target ◽

Copper Transporter ◽

Autophagic Degradation ◽

Vegfr2 Signaling ◽

P Type ◽

Golgi Network ◽

Deficient Mice

AbstractVEGFR2 (KDR/Flk1) signaling in endothelial cells (ECs) plays a central role in angiogenesis. The P-type ATPase transporter ATP7A regulates copper homeostasis, and its role in VEGFR2 signaling and angiogenesis is entirely unknown. Here, we describe the unexpected crosstalk between the Copper transporter ATP7A, autophagy, and VEGFR2 degradation. The functional significance of this Copper transporter was demonstrated by the finding that inducible EC-specific ATP7A deficient mice or ATP7A-dysfunctional ATP7Amut mice showed impaired post-ischemic neovascularization. In ECs, loss of ATP7A inhibited VEGF-induced VEGFR2 signaling and angiogenic responses, in part by promoting ligand-induced VEGFR2 protein degradation. Mechanistically, VEGF stimulated ATP7A translocation from the trans-Golgi network to the plasma membrane where it bound to VEGFR2, which prevented autophagy-mediated lysosomal VEGFR2 degradation by inhibiting autophagic cargo/adapter p62/SQSTM1 binding to ubiquitinated VEGFR2. Enhanced autophagy flux due to ATP7A dysfunction in vivo was confirmed by autophagy reporter CAG-ATP7Amut -RFP-EGFP-LC3 transgenic mice. In summary, our study uncovers a novel function of ATP7A to limit autophagy-mediated degradation of VEGFR2, thereby promoting VEGFR2 signaling and angiogenesis, which restores perfusion recovery and neovascularization. Thus, endothelial ATP7A is identified as a potential therapeutic target for treatment of ischemic cardiovascular diseases.

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Novel non‐canonical regulation of soluble VEGF/VEGFR2 signaling by mechanosensitive ion channel TRPV4 in endothelial cells

The FASEB Journal ◽

10.1096/fasebj.2018.32.1_supplement.703.2 ◽

2018 ◽

Vol 32 (S1) ◽

Author(s):

Anantha Koteswararao Kanugula ◽

Ravi K. Adapala ◽

Priya Midha ◽

Holly C. Cappelli ◽

Gary j. Meszaros ◽

...

Keyword(s):

Endothelial Cells ◽

Ion Channel ◽

Mechanosensitive Ion Channel ◽

Vegfr2 Signaling

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Tyrosine phosphatase PTP-MEG2 negatively regulates vascular endothelial growth factor receptor signaling and function in endothelial cells

AJP Cell Physiology ◽

10.1152/ajpcell.00415.2011 ◽

2012 ◽

Vol 303 (5) ◽

pp. C548-C553 ◽

Cited By ~ 10

Author(s):

Qin Hao ◽

Buka Samten ◽

Hong-Long Ji ◽

Z. Joe Zhao ◽

Hua Tang

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Tyrosine Phosphorylation ◽

Vascular Endothelial ◽

Wild Type ◽

Protein Tyrosine ◽

Vegfr2 Signaling ◽

And Function ◽

Endothelial Growth Factor

Protein tyrosine phosphorylation is a fundamental mechanism for diverse physiological processes, which is regulated by protein tyrosine kinases and protein tyrosine phosphatases (PTPs). In this study, we searched for protein substrates of PTP-MEG2 (also called PTPN9), a nonreceptor PTP, and investigated its function in endothelial cells (ECs). By using a PTP-MEG2 substrate-trapping DA mutant, we found that a couple of tyrosine-phosphorylated proteins were associated with the DA mutant but not wild-type PTP-MEG2 and that the association was enhanced by vascular endothelial growth factor (VEGF) in ECs. We further found that VEGF receptor 2 (VEGFR2) was coimmunopricipitated with the DA mutant but not wild-type PTP-MEG2. The VEGF-induced phosphorylation of VEGFR2 on Tyr1175, a critical autophosphorylation site for VEGFR2 signaling, was inhibited 70% by overexpression of wild-type PTP-MEG2 but was enhanced (2.2-fold) by the DA mutant of PTP-MEG2. We also found that PTP-MEG2 DA mutant preferentially associated with Janus kinase 1 (JAK1) but not with other JAK kinases (Tyk2 and JAK2) present in ECs and regulated JAK1 tyrosine phosphorylation. Lastly, the VEGF-induced signal transduction and the production of interleukin (IL)-6 were significantly enhanced by PTP-MEG2 knockdown in ECs, whereas the VEGF-induced IL-6 production was inhibited 50% by PTP-MEG2 overexpression. Thus we have indentified VEGFR2 as a PTP-MEG2 substrate, and our findings indicate that PTP-MEG2 is a negative regulator of VEGFR2 signaling and function in ECs.

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