Abstract 164: Endothelial Gab1 Limits Vascular Remodeling and Atherosclerosis Through Inhibition of Endothelial Inflammation

Objective: We have previously shown that docking protein Grb2-associated binder 1 (Gab1) is a mechano-effector protein in response to fluid shear stress and regulates postnatal angiogenesis. The aim of this study was to determine the in vivo role of endothelial Gab1 in flow-mediated vascular remodeling and atherosclerosis and explore the underlying mechanisms. Methods and Results: To determine the role of endothelial Gab1 in disturbed flow-induced vascular remodeling in vivo, we performed partial carotid artery ligation in Gab1 endothelium-restricted knockout (Gab1-ecKO) mice and wild-type (WT) littermates, and we observed that Gab1-ecKO mice resulted in increased intima-media thickness. To examine the role of endothelial Gab1 in atherosclerosis, we next crossed Gab1-ecKO mice with ApoE KO mice. After partial ligation, Gab1-ecKO;ApoE KO mice under high fat diet showed increased atherosclerotic lesion size compared to Gab1-WT;ApoE KO mice. The levels of proatherogenic genes intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and leukocyte infiltration were all increased in Gab1-ecKO;ApoE KO mice. Using loss- and gain-of-function studies in cultured human endothelial cells (ECs), we found that Gab1 depletion by siRNA augmented monocyte adhesion to ECs by increasing ICAM-1 and VCAM-1 expression in response to the proinflammatory cytokine TNF-α. Conversely, adenoviral overexpression of Gab1 inhibited TNFα-induced monocyte adhesion to ECs and upregulation of ICAM-1 and VCAM-1 in ECs. Conclusions: These results demonstrate that endothelial Gab1 represses disturbed flow-induced vascular remodeling and atherogenesis through inhibition of vascular inflammation. Our findings suggest that Gab1 activation might represent novel approaches for the treatment of vascular diseases, including intimal hyperplasia and atherosclerosis.