共 39 条
Selective inhibition of vascular endothelial growth factor receptor-2 (VEGXR-2) identifies a central role for VEGFR-2 in human aortic endothelial cell responses to VEGF
被引:34
作者:

Endo, A
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机构:
Natl Cardiovasc Ctr, Inst Res, Dept Struct Anal, Suita, Osaka 5658565, Japan Natl Cardiovasc Ctr, Inst Res, Dept Struct Anal, Suita, Osaka 5658565, Japan

Fukuhara, S
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Natl Cardiovasc Ctr, Inst Res, Dept Struct Anal, Suita, Osaka 5658565, Japan Natl Cardiovasc Ctr, Inst Res, Dept Struct Anal, Suita, Osaka 5658565, Japan

Masuda, M
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Natl Cardiovasc Ctr, Inst Res, Dept Struct Anal, Suita, Osaka 5658565, Japan Natl Cardiovasc Ctr, Inst Res, Dept Struct Anal, Suita, Osaka 5658565, Japan

Ohmori, T
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Natl Cardiovasc Ctr, Inst Res, Dept Struct Anal, Suita, Osaka 5658565, Japan Natl Cardiovasc Ctr, Inst Res, Dept Struct Anal, Suita, Osaka 5658565, Japan

Mochizuki, N
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Natl Cardiovasc Ctr, Inst Res, Dept Struct Anal, Suita, Osaka 5658565, Japan Natl Cardiovasc Ctr, Inst Res, Dept Struct Anal, Suita, Osaka 5658565, Japan
机构:
[1] Natl Cardiovasc Ctr, Inst Res, Dept Struct Anal, Suita, Osaka 5658565, Japan
关键词:
VEGF receptor;
inhibitor;
angiogenesis;
D O I:
10.1081/RRS-120025567
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
Vascular endothelial growth factor receptors (VEGFR) are considered essential for angiogenesis. The VEGFR-family proteins consist of VEGFR-1/Flt-1, VEGFR-2/ KDR/Flk- 1, and VEGFR-3/Flt-4. Among these, VEGFR-2 is thought to be principally responsible for angiogenesis. However, the precise role of VEGFRs1-3 in endothelial cell biology and angiogenesis remains unclear due in part to the lack of VEGFR-specific inhibitors. We used the newly described, highly selective anilinoquinazoline inhibitor of VEGFR-2 tyrosine kinase, ZM323881 (5-[[7-(benzyloxy) quinazolin-4- yl]amino]-4-fluoro-2-methylphenol), to explore the role of VEGFR-2 in endothelial cell function. Consistent with its reported effects on VEGFR-2 [IC(50) < 2 nM], ZM323881 inhibited activation of VEGFR-2, but not of VEGFR-1, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), or hepatocyte growth factor (HGF) receptor., We studied the effects of VEGF on human aortic endothelial cells (HAECs), which express VEGFR-1 and VEGFR-2, but not VEGFR-3, in the absence or presence of ZM323881. Inhibition of VEGFR-2 blocked activation of extracellular regulated-kinase, p38, Akt, and endothelial nitric oxide synthetase (eNOS) by VEGF, but did not inhibit p38 activation by the VEGFR-1-specific ligand, placental growth factor (PIGF). Inhibition of VEGFR-2 also perturbed VEGF-induced membrane extension, cell migration, and tube formation by HAECs. Vascular endothelial growth factor receptor-2 inhibition also reversed VEGF-stimulated phosphorylation of CrkII and its Src homology 2 (SH2)-binding protein p130(Cas) which are known to play a pivotal role in regulating endothelial cell migration. Inhibition of VEGFR-2 thus blocked all VEGF-induced endothelial cellular responses tested, supporting that the catalytic activity of VEGFR-2 is critical for VEGF signaling and/or that VEGFR-2 may function in a heterodimer with VEGFR-1 in human vascular endothelial cells.
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页码:239 / 254
页数:16
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