| First Author | Lakshmikanthan S | Year | 2011 |
| Journal | Blood | Volume | 118 |
| Issue | 7 | Pages | 2015-26 |
| PubMed ID | 21636859 | Mgi Jnum | J:176941 |
| Mgi Id | MGI:5293211 | Doi | 10.1182/blood-2011-04-349282 |
| Citation | Lakshmikanthan S, et al. (2011) Rap1 promotes VEGFR2 activation and angiogenesis by a mechanism involving integrin alphavbeta. Blood 118(7):2015-26 |
| abstractText | 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 alpha(v)beta(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 alpha(v)beta(3). These results provide a novel insight into the role of Rap1 in VEGF signaling in ECs. |
