Faculty Collaboration Database

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

Scopus ID

2-s2.0-80051865329 (requires institutional sign-in at Scopus site)   108 Citations

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

Author

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