Plasminogen Activator Inhibitor-1 Inhibits Angiogenic Signaling by Uncoupling Vascular Endothelial Growth Factor Receptor-2-αVβ3 Integrin Cross Talk. Issue 1 (January 2015)

• Record Type: Journal Article
• Authors: Wu, Jianbo; Strawn, Tammy L.; Luo, Mao; Wang, Liqun; Li, Rong; Ren, Meiping; Xia, Jiyi; Zhang, Zhuo; Ma, Weizhong; Luo, Tingting; Lawrence, Daniel A.; Fay, William P.
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 35:Issue 1(2015)
• Publication Date: 2015-01
• Subjects: Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.114.304554
• Languages: English
• ISSNs: 1079-5642

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Objective—</title> <p>Plasminogen activator inhibitor-1 (PAI-1) regulates angiogenesis via effects on extracellular matrix proteolysis and cell adhesion. However, no previous study has implicated PAI-1 in controlling vascular endothelial growth factor (VEGF) signaling. We tested the hypothesis that PAI-1 downregulates VEGF receptor-2 (VEGFR-2) activation by inhibiting a vitronectin-dependent cooperative binding interaction between VEGFR-2 and α<sub>V</sub>β<sub>3</sub>.</p> </sec> <sec> <title>Approach and Results—</title> <p>We studied effects of PAI-1 on VEGF signaling in human umbilical vein endothelial cells. PAI-1 inhibited VEGF-induced phosphorylation of VEGFR-2 in human umbilical vein endothelial cells grown on vitronectin, but not on fibronectin or collagen. PAI-1 inhibited the binding of VEGFR-2 to β<sub>3</sub> integrin, VEGFR-2 endocytosis, and intracellular signaling pathways downstream of VEGFR-2. The anti-VEGF effect of PAI-1 was mediated by 2 distinct pathways, one requiring binding to vitronectin and another requiring binding to very low-density lipoprotein receptor. PAI-1 inhibited VEGF-induced angiogenesis in vitro and in vivo, and pharmacological inhibition of PAI-1 promoted collateral arteriole development and recovery of hindlimb perfusion after femoral artery interruption.</p> </sec> <sec> <title>Conclusions—</title> <p>PAI-1 inhibits activation of VEGFR-2 by VEGF by disrupting a vitronectin-dependent proangiogenic binding interaction involving α<sub>V</sub>β<sub>3</sub> and VEGFR-2. These results broaden our understanding of the roles of PAI-1, vitronectin, and endocytic receptors in regulating VEGFR-2 activation and suggest novel therapeutic strategies for regulating VEGF signaling.</p> </sec> </abstract>