title: Dedicator of cytokinesis 2, a novel regulator for smooth muscle phenotypic modulation and vascular remodeling.
abstract: BACKGROUND
  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.
  
  
  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.
authors: From the Department of Physiology and Pharmacology, University of Georgia, Athens (X.G., N.S., X.-B.C., S.-Y.C.); Department of Cardiology, Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China (J.-N.W., S.-Y.C.); and Department of Immunobiology and Neuroscience, Kyushu University, Fukuoka, Japan (Y.F.).
authors: Xia
authors: X
authors: Guo
authors: From the Department of Physiology and Pharmacology, University of Georgia, Athens (X.G., N.S., X.-B.C., S.-Y.C.); Department of Cardiology, Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China (J.-N.W., S.-Y.C.); and Department of Immunobiology and Neuroscience, Kyushu University, Fukuoka, Japan (Y.F.).
authors: Ning
authors: N
authors: Shi
authors: From the Department of Physiology and Pharmacology, University of Georgia, Athens (X.G., N.S., X.-B.C., S.-Y.C.); Department of Cardiology, Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China (J.-N.W., S.-Y.C.); and Department of Immunobiology and Neuroscience, Kyushu University, Fukuoka, Japan (Y.F.).
authors: Xiao-Bing
authors: XB
authors: Cui
authors: From the Department of Physiology and Pharmacology, University of Georgia, Athens (X.G., N.S., X.-B.C., S.-Y.C.); Department of Cardiology, Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China (J.-N.W., S.-Y.C.); and Department of Immunobiology and Neuroscience, Kyushu University, Fukuoka, Japan (Y.F.).
authors: Jia-Ning
authors: JN
authors: Wang
authors: From the Department of Physiology and Pharmacology, University of Georgia, Athens (X.G., N.S., X.-B.C., S.-Y.C.); Department of Cardiology, Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China (J.-N.W., S.-Y.C.); and Department of Immunobiology and Neuroscience, Kyushu University, Fukuoka, Japan (Y.F.).
authors: Yoshinori
authors: Y
authors: Fukui
authors: From the Department of Physiology and Pharmacology, University of Georgia, Athens (X.G., N.S., X.-B.C., S.-Y.C.); Department of Cardiology, Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China (J.-N.W., S.-Y.C.); and Department of Immunobiology and Neuroscience, Kyushu University, Fukuoka, Japan (Y.F.). sc229@uga.edu.
authors: Shi-You
authors: SY
authors: Chen
mesh_terms: D000818:Animals; D000077214:Becaplermin; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006965:Hyperplasia; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058426:Neointima; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D066253:Vascular Remodeling / Q000187:drug effects; D020830:rac1 GTP-Binding Protein; D000099251:Myocardin
chemical_list: D000077214:Becaplermin; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D020574:Proto-Oncogene Proteins c-sis; D026362:Serum Response Factor; D015534:Trans-Activators; D020830:rac1 GTP-Binding Protein; D000099251:Myocardin; C471356:DOCK2 protein, mouse; C000599479:DOCK2 protein, rat; C000715468:Klf4 protein, mouse; C000715469:Klf4 protein, rat
keywords: cell proliferation; dedicator of cytokinesis 2; vascular remodeling