Differential αv integrin–mediated Ras-ERK signaling during two pathways of angiogenesis

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Abstract
Antagonists of αvβ3 and αvβ5 disrupt angiogenesis in response to bFGF and VEGF, respectively. Here, we show that these αv integrins differentially contribute to sustained Ras-extracellular signal–related kinase (Ras-ERK) signaling in blood vessels, a requirement for endothelial cell survival and angiogenesis. Inhibition of FAK or αvβ5 disrupted VEGF-mediated Ras and c-Raf activity on the chick chorioallantoic membrane, whereas blockade of FAK or integrin αvβ3 had no effect on bFGF-mediated Ras activity, but did suppress c-Raf activation. Furthermore, retroviral delivery of active Ras or c-Raf promoted ERK activity and angiogenesis, which anti-αvβ5 blocked upstream of Ras, whereas anti-αvβ3 blocked downstream of Ras, but upstream of c-Raf. The activation of c-Raf by bFGF/αvβ3 not only depended on FAK, but also required p21-activated kinase-dependent phosphorylation of serine 338 on c-Raf, whereas VEGF-mediated c-Raf phosphorylation/activation depended on Src, but not Pak. Thus, integrins αvβ3 and αvβ5 differentially regulate the Ras-ERK pathway, accounting for distinct vascular responses during two pathways of angiogenesis.