Dedicator of Cytokinesis 2, A Novel Regulator for Smooth Muscle Phenotypic Modulation and Vascular Remodeling

Rationale:Vascular smooth muscle cell (SMC) phenotypic modulation and vascular remodeling contribute to the development of several vascular disorders such as restenosis after angioplasty, transplant vasculopathy, and atherosclerosis. The mechanisms underlying these processes, however, remain largely unknown. Objective:The objective of this study is to determine the role of dedicator of cytokinesis 2 (DOCK2) in SMC phenotypic modulation and vascular remodeling. Methods and Results:Platelet-derived growth factor-BB induced DOCK2 expression while modulating SMC phenotype. DOCK2 deficiency diminishes platelet-derived growth factor-BB or serum-induced downregulation of SMC markers. Conversely, DOCK2 overexpression inhibits SMC marker expression in primary cultured SMC. Mechanistically, DOCK2 inhibits myocardin expression, blocks serum response factor nuclear location, attenuates myocardin binding to serum response factor, and thus attenuates myocardin-induced smooth muscle marker promoter activity. Moreover, D...