The adaptor protein Shc integrates growth factor and ECM signaling during postnatal angiogenesis

Angiogenesis requires integration of cues from growth factors, extracellular matrix proteins and their receptors in endothelial cells. Here, we show that the adaptor protein Shc is required for angiogenesis in zebrafish, mice, and in cell culture models. Shc knockdown embryos show defects in intersegmental vessel sprouting in the zebrafish trunk. Shc flox/flox; Tie2-Cre mice display reduced angiogenesis in the retinal neovascularization model and in response to VEGF in the Matrigel plug assay in vivo. Functional studies reveal a model whereby Shc is required for integrin-mediated spreading and migration specifically on fibronectin, as well as EC survival in response to VEGF. Mechanistically, Shc is required for activation of the Akt pathway downstream of both integrin and VEGF signaling as well as for integration of signals from these two receptors when cells are grown on fibronectin. Thus, we have identified a unique mechanism in which signals from two critical angiogenic signaling axes, integrins and VEGFR-2, converge at Shc to regulate postnatal angiogenesis.