Dedicator of cytokinesis 2, a novel regulator for vascular smooth muscle cell phenotype modulation and vascular remodeling (670.3)

Abstract

The objective of this study is to determine the role of dedicator of cytokinesis 2 (DOCK2) in vascular smooth muscle cell (VSMC) phenotypic modulation and vascular remodeling. Platelet‐derived growth factor‐BB (PDGF‐BB) induced DOCK2 expression while modulating VSMC phenotype as indicated by reduced VSMC marker expression. DOCK2 overexpression inhibited while DOCK2 knockout enhanced SMC marker gene expression in primary VSMC. Mechanistically, DOCK2 regulated VSMC phenotype through suppression myocardin/serum response factor (SRF)‐mediated transcription of VSMC marker genes. DOCK2 blocked myocardin, but not SRF expression and inhibited myocardin‐activated α‐SMA promoter activity. DOCK2 was also essential for PDGF‐BB‐induced VSMC proliferation and migration. DOCK2 stimulated VSMC migration via induction of focal adhesion contact and stress fiber formation. By using both rat carotid artery balloon‐injury and mouse ligation injury models, we observed that DOCK2 was highly induced in injury‐induced neointima. Knockdown of DOCK2 dramatically inhibited the neointima formation by 60%. Most importantly, knockout of DOCK2 in mice markedly blocked ligation‐induced intimal hyperplasia. These data demonstrate that DOCK2 plays an important role in VSMC phenotypic modulation and vascular lesion formation following vascular injury.Grant Funding Source: HL093429 and HL107526 to Shi‐You Chen, Pre‐doctoral Fellowship Award 12PRE12030180 to Xia Guo