Fibroblast Growth Factor 12 Is a Novel Regulator of Vascular Smooth Muscle Cell Plasticity and Fate
Fibroblast Growth Factor 12 Is a Novel Regulator of Vascular Smooth Muscle Cell Plasticity and Fate
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DOI：
10.1161/atvbaha.116.308017
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发表时间：
2016-09-01
影响因子：
8.7
通讯作者：
Suh, Wonhee
中科院分区：
文献类型：
--
作者：
Song, Sun-Hwa;Kim, Kyungjong;Suh, Wonhee
目的血管平滑肌细胞(VSMCs)根据环境变化调节其合成和收缩状态的表型，这种调节在再狭窄和动脉粥样硬化的发病机制中起着至关重要的作用。在此，我们确定成纤维细胞生长因子12(FGF12)是一种新的VSMC表型转换的关键调节因子。方法与结果利用小鼠模型和人类标本，我们发现FGF12在正常血管壁的收缩VSMCs中高表达，而在损伤和动脉粥样硬化的合成VSMCs中表达下调。在人VSMCs中，血小板衍生生长因子-BB在转录水平上抑制FGF12的表达。功能获得和功能丧失实验表明，FGF12是诱导和维持VSMC静止和收缩表型的必要条件和充分条件。FGF12通过P53途径抑制细胞增殖，上调VSMC系分化的关键因子，如肌钙蛋白和血清反应因子。这种FGF12诱导的表型改变是由p38MAPK(丝裂原活化蛋白激酶)途径介导的。此外，FGF12还促进了小鼠胚胎干细胞的分化和人皮肤成纤维细胞向SMC样细胞的转分化。此外，腺病毒感染FGF12显著减少了大鼠颈动脉损伤模型中新生内膜的增殖。有趣的是，本研究发现属于成纤维细胞生长因子家族的FGF12强烈诱导静止和收缩的VSMC表型，并直接促进VSMC的谱系分化。这些新发现表明，FGF12可能成为治疗再狭窄和动脉粥样硬化的新靶点。
Objective Vascular smooth muscle cells (VSMCs) modulate their phenotype between synthetic and contractile states in response to environmental changes; this modulation plays a crucial role in the pathogenesis of restenosis and atherosclerosis. Here, we identified fibroblast growth factor 12 (FGF12) as a novel key regulator of the VSMC phenotype switch.Approach and Results Using murine models and human specimens, we found that FGF12 was highly expressed in contractile VSMCs of normal vessel walls but was downregulated in synthetic VSMCs from injured and atherosclerotic vessels. In human VSMCs, FGF12 expression was inhibited at the transcriptional level by platelet-derived growth factor-BB. Gain- and loss-of-function experiments showed that FGF12 was both necessary and sufficient for inducing and maintaining the quiescent and contractile phenotypes of VSMCs. FGF12 inhibited cell proliferation through the p53 pathway and upregulated the key factors involved in VSMC lineage differentiation, such as myocardin and serum response factor. Such FGF12-induced phenotypic change was mediated by the p38 MAPK (mitogen-activated protein kinase) pathway. Moreover, FGF12 promoted the differentiation of mouse embryonic stem cells and the transdifferentiation of human dermal fibroblasts into SMC-like cells. Furthermore, adenoviral infection of FGF12 substantially decreased neointima hyperplasia in a rat carotid artery injury model.Conclusions In general, FGF family members induce a synthetic VSMC phenotype. Interestingly, the present study showed the unanticipated finding that FGF12 belonging to FGF family, strongly induced the quiescent and contractile VSMC phenotypes and directly promoted VSMC lineage differentiation. These novel findings suggested that FGF12 could be a new therapeutic target for treating restenosis and atherosclerosis.