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

• Published in: Circulation research 2015-05, Vol.116 (10), p.e71-e80
• Main Authors: Guo, Xia, Shi, Ning, Cui, Xiao-Bing, Wang, Jia-Ning, Fukui, Yoshinori, Chen, Shi-You
• Format: Article
• Language: English
• Subjects: Animals; Becaplermin; Carotid Artery Injuries - genetics; Carotid Artery Injuries - metabolism; Carotid Artery Injuries - pathology; Cells, Cultured; Disease Models, Animal; Gene Expression Regulation; GTPase-Activating Proteins - deficiency; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Hyperplasia; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Male; Mice, Knockout; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Neointima; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phenotype; Proto-Oncogene Proteins c-sis - pharmacology; rac1 GTP-Binding Protein; Rats, Sprague-Dawley; RNA Interference; Serum Response Factor - genetics; Serum Response Factor - metabolism; Signal Transduction; Trans-Activators - genetics; Trans-Activators - metabolism; Transfection; Vascular Remodeling - drug effects
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.116.305863

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, DOCK2 and Kruppel-like factor 4 cooperatively inhibit myocardin–serum response factor interaction. In a rat carotid artery balloon-injury model, DOCK2 is induced in media layer SMC initially and neointima SMC subsequently after 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 after vascular injury. Therefore, targeting DOCK2 may be a potential therapeutic strategy for the prevention of vascular remodeling in proliferative vascular diseases.