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Rap1 promotes VEGFR2 activation and angiogenesis by a mechanism involving integrin αvβ₃. Blood 2011 Aug 18;118(7):2015-26

Date

06/04/2011

Pubmed ID

21636859

Pubmed Central ID

PMC3158727

DOI

10.1182/blood-2011-04-349282

Abstract

Vascular endothelial growth factor (VEGF) acting through VEGF receptor 2 (VEGFR2) on endothelial cells (ECs) is a key regulator of angiogenesis, a process essential for wound healing and tumor metastasis. Rap1a and Rap1b, 2 highly homologous small G proteins, are both required for angiogenesis in vivo and for normal EC responses to VEGF. Here we sought to determine the mechanism through which Rap1 promotes VEGF-mediated angiogenesis. Using lineage-restricted Rap1-knockout mice we show that Rap1-deficiency in endothelium leads to defective angiogenesis in vivo, in a dose-dependent manner. Using ECs obtained from Rap1-deficient mice we demonstrate that Rap1b promotes VEGF-VEGFR2 kinase activation and regulates integrin activation. Importantly, the Rap1b-dependent VEGF-VEGFR2 activation is in part mediated via integrin α(v)β(3). Furthermore, in an in vivo model of zebrafish angiogenesis, we demonstrate that Rap1b is essential for the sprouting of intersomitic vessels, a process known to be dependent on VEGF signaling. Using 2 distinct pharmacologic VEGFR2 inhibitors we show that Rap1b and VEGFR2 act additively to control angiogenesis in vivo. We conclude that Rap1b promotes VEGF-mediated angiogenesis by promoting VEGFR2 activation in ECs via integrin α(v)β(3). These results provide a novel insight into the role of Rap1 in VEGF signaling in ECs.

Author List

Lakshmikanthan S, Sobczak M, Chun C, Henschel A, Dargatz J, Ramchandran R, Chrzanowska-Wodnicka M

Authors

Magdalena Chrzanowska PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Ramani Ramchandran PhD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cells, Cultured
Down-Regulation
Endothelial Cells
Gene Deletion
Integrin alphaVbeta3
Mice
Mice, Inbred C57BL
Neovascularization, Physiologic
Vascular Endothelial Growth Factor Receptor-2
Zebrafish
rap GTP-Binding Proteins
rap1 GTP-Binding Proteins
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d