Dedicator of cytokinesis 2, a novel regulator for smooth muscle phenotypic modulation and vascular remodeling.
Dedicator of cytokinesis 2, a novel regulator for smooth muscle phenotypic modulation and vascular remodeling.
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DOI：
10.1161/circresaha.116.305863
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发表时间：
2015-05-08
影响因子：
20.1
通讯作者：
Chen SY
中科院分区：
文献类型：
--
作者：
Guo X;Shi N;Cui XB;Wang JN;Fukui Y;Chen SY
血管平滑肌细胞（SMC）表型调节和血管重塑有助于许多血管疾病的发展，如血管成形术后再狭窄、移植血管病变和动脉粥样硬化。然而，这些过程背后的机制在很大程度上仍是未知的。本研究的目的是确定细胞分裂奉献因子2 （DOCK2）在SMC表型调节和血管重塑中的作用。血小板衍生生长因子- bb （PDGF-BB）在调节SMC表型的同时诱导DOCK2表达。DOCK2缺乏减少PDGF-BB或血清诱导的SMC标记下调。相反，在原代培养的SMC中，DOCK2过表达抑制SMC标记物的表达。在机制上，DOCK2抑制了心肌素的表达，阻断了SRF的核定位，减弱了心肌素与SRF的结合，从而减弱了心肌素诱导的平滑肌标志物启动子活性。此外，DOCK2和kruppel样因子4共同抑制了心肌素- srf的相互作用。在大鼠颈动脉球囊损伤模型中，DOCK2在血管损伤后首先在中膜SMC中被诱导，随后在新内膜SMC中被诱导。敲低DOCK2可显著抑制60%的新生内膜形成。最重要的是，敲除小鼠DOCK2可显著阻断结扎诱导的内膜增生，同时恢复SMC收缩蛋白的表达。我们的研究发现DOCK2是血管损伤后SMC表型调节和血管病变形成的新调节剂。因此，靶向DOCK2可能是预防增殖性血管疾病血管重构的潜在治疗策略。
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. The objective of this study is to determine the role of dedicator of cytokinesis 2 (DOCK2) in SMC phenotypic modulation and vascular remodeling. 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. 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.