The downstream network of STAT6 in promoting vascular smooth muscle cell phenotypic switch and neointimal formation
The downstream network of STAT6 in promoting vascular smooth muscle cell phenotypic switch and neointimal formation
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DOI：
10.1002/cbin.12056
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发表时间：
2023-06-11
影响因子：
3.9
通讯作者：
Yang，Xiangdong
中科院分区：
文献类型：
--
作者：
Ding，Suling;Wang，Xiangfei;Yang，Xiangdong
血管平滑肌细胞过度增殖引起的内膜增厚是心血管疾病（包括再狭窄）的核心病理过程。血管损伤后，血管平滑肌细胞会发生表型转换，从完全分化、低增殖率的表型转换为更促增殖、促迁移和不完全分化的状态。缺乏对将血管损伤刺激与VSMC表型转换偶联的分子途径的充分理解在很大程度上限制了治疗内膜增生相关疾病的药物疗法的开发。信号转导子和转录激活子6（STAT 6）在调节多种细胞特别是巨噬细胞增殖和分化中的作用已被广泛研究，但其在血管损伤后再狭窄中的病理生理作用及其靶基因尚不清楚。在目前的工作中，观察到Stat 6 −/−小鼠在颈动脉损伤后与Stat 6 +/+小鼠相比表现出较轻的内膜增生。位于损伤血管壁的VSMCs中STAT 6的表达上调。STAT 6缺失导致VSMCs增殖和迁移能力下降，而过表达STAT 6则促进VSMCs增殖和迁移，同时减少VSMCs标志基因的表达和组织化的应力纤维。STAT 6在小鼠VSMC中的作用在人主动脉SMC中是保守的。RNA深度测序和实验验证显示，LncRNA C7 orf 69/LOC 100996318-miR-370 - 3 p/FOXO 1-ER应激信号传导是介导STAT 6在VSMC中促去分化作用的下游网络。这些发现拓宽了我们对血管病理分子的理解，并为各种增生性血管疾病的治疗带来了光明。
Intimal thickening caused by the excessive multiplication of vascular smooth muscle cells (VSMCs) is the pathological process central to cardiovascular diseases, including restenosis. In response to vascular injury, VSMCs would undergo phenotypic switching from a fully differentiated, low proliferative rate phenotype to a more pro‐proliferative, promigratory, and incompletely‐differentiated state. The lack of a full understanding of the molecular pathways coupling the vascular injury stimuli to VSMCs phenotype switching largely limits the development of medical therapies for treating intima hyperplasia‐related diseases. The role of signal transducers and activators of transcription 6 (STAT6) in modulating the proliferation and differentiation of various cell types, especially macrophage, has been well investigated, but little is known about its pathophysiological role and target genes in restenosis after vascular injury. In the present work, Stat6−/−mice were observed to exhibit less severe intimal hyperplasia compared with Stat6+/+mice after carotid injury. The expression of STAT6 was upregulated in VSMCs located in the injured vascular walls. STAT6 deletion leads to decreased proliferation and migration of VSMCs while STAT6 overexpression enhances the proliferation and migration of VSMCs companies with reduced expression of VSMCs marker genes and organized stress fibers. The effect of STAT6 in mouse VSMCs was conserved in human aortic SMCs. RNA‐deep‐sequencing and experiments verification revealed LncRNA C7orf69/LOC100996318‐miR‐370‐3p/FOXO1‐ER stress signaling as the downstream network mediating the pro‐dedifferentiation effect of STAT6 in VSMCs. These findings broaden our understanding of vascular pathological molecules and throw a beam of light on the therapy of a variety of proliferative vascular diseases.