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 contributes to the development of a number of 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 (PDGF-BB) induced DOCK2 expression while modulating SMC phenotype. DOCK2 deficiency diminishes PDGF-BB or serum-induced down regulation of SMC markers. Conversely, DOCK2 overexpression inhibits SMC marker expression in primary cultured SMC. Mechanistically, DOCK2 inhibits myocardin expression, blocks SRF nuclear location, attenuates myocardin binding to SRF, and thus attenuates myocardin-induced smooth muscle marker promoter activity. Moreover, DOCK2 and Kruppel-like factor 4 cooperatively inhibit myocardin-SRF interaction. In a rat carotid artery balloon-injury model, DOCK2 is induced in media layer SMC initially and neointima SMC subsequently following vascular injury. Knockdown of DOCK2 dramatically inhibits the neointima formation by 60%. Most importantly, knockout of DOCK2 in mice markedly blocks ligation-induced intimal hyperplasia while restoring SMC contractile protein expression.
Conclusions: Our studies identified DOCK2 as a novel regulator for SMC phenotypic modulation and vascular lesion formation following vascular injury. Therefore, targeting DOCK2 may be a potential therapeutic strategy for the prevention of vascular remodeling in proliferative vascular diseases.
- Dedicator of cytokinesis 2
- vascular remodeling
- vascular smooth muscle
- Received December 13, 2014.
- Revision received March 13, 2015.
- Accepted March 18, 2015.