Smooth muscle cell-specific fibronectin-EDA mediates phenotypic switching and neointimal hyperplasia
Smooth muscle cell-specific fibronectin-EDA mediates phenotypic switching and neointimal hyperplasia
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DOI：
10.1172/jci124708
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发表时间：
2020-01-01
影响因子：
15.9
通讯作者：
Chauhan, Anil K.
中科院分区：
文献类型：
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作者：
Jain, Manish;Dhanesha, Nirav;Chauhan, Anil K.
含有额外结构域A的纤连蛋白剪接变体（Fn-EDA）与血管损伤后的平滑肌细胞（SMC）相关。SMC衍生的Fn-EDA在SMC表型转换中的作用或其在新生内膜增生中的意义尚不清楚。在此，使用裸金属支架的人冠状动脉切片，我们证明了在富含SMC的新生内膜和支柱周围区域附近Fn-EDA的表达。在小鼠中，Fn-EDA与损伤的颈动脉的新生内膜中的SMC共定位，并通过增强SMC增殖和迁移促进高脂血症共病条件下的新生内膜形成。未观察到基于性别的差异。机制研究表明，Fn-EDA介导的整合素和TLR 4依赖的增殖和迁移，通过激活FAK/Src和Akt 1/mTOR信号，分别。在SMC中特异性缺失Fn-EDA，而不是在内皮细胞中，减少内膜增生并抑制SMC合成表型，同时降低Akt 1/mTOR信号传导。靶向人主动脉SMC中的Fn-EDA抑制合成表型并下调Akt 1/mTOR信号传导。这些结果表明，SMC衍生的Fn-EDA增强人和小鼠主动脉SMC中的表型转换和小鼠中的新生内膜增生。我们认为靶向Fn-EDA可以作为一种潜在的治疗策略来减少新生内膜增生。
Fibronectin-splice variant containing extra domain A (Fn-EDA) is associated with smooth muscle cells (SMCs) following vascular injury. The role of SMC-derived Fn-EDA in SMC phenotypic switching or its implication in neointimal hyperplasia remains unclear. Herein, using human coronary artery sections with a bare metal stent, we demonstrate the expression of Fn-EDA in the vicinity of SMC-rich neointima and peri-strut areas. In mice, Fn-EDA colocalizes with SMCs in the neointima of injured carotid arteries and promotes neointima formation in the comorbid condition of hyperlipidemia by potentiating SMC proliferation and migration. No sex-based differences were observed. Mechanistic studies suggested that Fn-EDA mediates integrin- and TLR4-dependent proliferation and migration through activation of FAK/Src and Akt1/mTOR signaling, respectively. Specific deletion of Fn-EDA in SMCs, but not in endothelial cells, reduced intimal hyperplasia and suppressed the SMC synthetic phenotype concomitant with decreased Akt1/mTOR signaling. Targeting Fn-EDA in human aortic SMCs suppressed the synthetic phenotype and downregulated Akt1/mTOR signaling. These results reveal that SMC-derived Fn-EDA potentiates phenotypic switching in human and mouse aortic SMCs and neointimal hyperplasia in the mouse. We suggest that targeting Fn-EDA could be explored as a potential therapeutic strategy to reduce neointimal hyperplasia.