The adaptor protein Shc is a critical regulator of angiogenic and shear stress signaling in endothelial cells.

摘要

Endothelial cells (ECs), which form the lining of blood vessels, actively participate in many aspects of cardiovascular development and pathologies such as cancer and atherosclerosis. Vascular ECs are unique in the diverse array of signals that they are capable of sensing from soluble growth factors, immobile extracellular matrix (ECM) proteins and mechanical forces. Studying EC responses to this array of signals will enhance our understanding of the etiology of prevalent diseases such as cancer and atherosclerosis and lead to improved treatments.;Shc is an evolutionarily conserved adaptor protein that mediates signaling cascades downstream of activated receptors and is essential for development of the cardiovascular system. This dissertation focuses on defining the roles that Shc plays in EC responses to angiogenic cues and mechanical force.;Angiogenesis, the growth of new blood vessels from pre-existing vessels, is important during embryonic development as well as in adults for wound healing and tumorigenesis. Using loss-of-function experiments in the mouse and zebrafish, we found that Shc is required for sprouting angiogenesis in vivo. Shc mediates signaling from integrins and VEGF receptors which is required for haptotaxis, survival and sprouting. Interestingly, Shc integrates VEGF and ECM signaling as VEGF-induced survival requires Shc specifically on fibronectin.;Fluid shear stress, the frictional force from blood flowing over ECs, regulates EC function and allows vessels to respond to changes in tissue physiology but also contributes to vessel pathogenesis such as atherosclerosis. We have shown that Shc is required for transducing shear stress signaling directly downstream of the 'mechanosensory complex'. Shc is required for induction of the inflammatory response that is activated by disturbed shear stress and underlies the development of atherosclerotic plaques. Additionally, Shc is required in mice for shear-induced collateral artery remodeling and arterial specification during arteriogenesis.;Together, Shc plays an important signaling function in ECs and enables ECs to dynamically respond to angiogenic and mechanical stimulation from their environment.