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Arterioscler Thromb Vasc Biol. 2015 Jan;35(1):111-20. doi: 10.1161/ATVBAHA.114.304554. Epub 2014 Nov 6.

Plasminogen activator inhibitor-1 inhibits angiogenic signaling by uncoupling vascular endothelial growth factor receptor-2-αVβ3 integrin cross talk.

Author information

1
From the Departments of Internal Medicine and Medical Pharmacology and Physiology (J.W., T.L.S., M.L., W.P.F.), the Research Service, Harry S. Truman Memorial Veterans Hospital (W.P.F.), University of Missouri School of Medicine, Columbia; the Drug Discovery Research Center, Luzhou Medical College, Luzhou, Sichuan, China (J.W., M.L., L.W., R.L., M.R., J.X., Z.Z., W.M., T.L.); and the Department of Internal Medicine, University of Michigan Medical School, Ann Arbor (D.A.L.). wuji@missouri.edu.
2
From the Departments of Internal Medicine and Medical Pharmacology and Physiology (J.W., T.L.S., M.L., W.P.F.), the Research Service, Harry S. Truman Memorial Veterans Hospital (W.P.F.), University of Missouri School of Medicine, Columbia; the Drug Discovery Research Center, Luzhou Medical College, Luzhou, Sichuan, China (J.W., M.L., L.W., R.L., M.R., J.X., Z.Z., W.M., T.L.); and the Department of Internal Medicine, University of Michigan Medical School, Ann Arbor (D.A.L.).

Abstract

OBJECTIVE:

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 αVβ3.

APPROACH AND RESULTS:

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 β3 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.

CONCLUSIONS:

PAI-1 inhibits activation of VEGFR-2 by VEGF by disrupting a vitronectin-dependent proangiogenic binding interaction involving αVβ3 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.

KEYWORDS:

plasminogen activator inhibitor-1; vascular endothelial growth factor A; very low-density lipoprotein receptor; vitronectin

PMID:
25378411
PMCID:
PMC4270947
DOI:
10.1161/ATVBAHA.114.304554
[Indexed for MEDLINE]
Free PMC Article

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