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.

中文翻译：

---

平滑肌细胞特异性纤连蛋白-EDA介导表型转换和新内膜增生

包含额外结构域A（Fn-EDA）的纤连蛋白剪接变体与血管损伤后的平滑肌细胞（SMC）相关。尚不清楚SMC衍生的Fn-EDA在SMC表型转换中的作用或其在新内膜增生中的作用。在本文中，使用带有裸金属支架的人冠状动脉切片，我们证明了Fn-EDA在富含SMC的新内膜和支柱周围区域的表达。在小鼠中，Fn-EDA与SMC共同定位在受损颈动脉的新内膜中，并通过增强SMC的增殖和迁移，在高脂血症合并症中促进新内膜的形成。没有观察到基于性别的差异。机理研究表明，Fn-EDA分别通过激活FAK / Src和Akt1 / mTOR信号传导介导整合素和TLR4依赖性增殖和迁移。Fn-EDA在SMCs中有特异性缺失，但在内皮细胞中却没有，从而减少了内膜增生并抑制了SMC合成表型，同时降低了Akt1 / mTOR信号传导。在人主动脉SMC中靶向Fn-EDA可抑制合成表型并下调Akt1 / mTOR信号传导。这些结果表明，SMC衍生的Fn-EDA增强了人和小鼠主动脉SMC的表型转换和小鼠的新内膜增生。我们建议针对Fn-EDA可以探索为减少新内膜增生的潜在治疗策略。这些结果表明，SMC衍生的Fn-EDA增强了人和小鼠主动脉SMC的表型转换和小鼠的新内膜增生。我们建议针对Fn-EDA可以探索为减少新内膜增生的潜在治疗策略。这些结果表明，SMC衍生的Fn-EDA增强了人和小鼠主动脉SMC的表型转换和小鼠的新内膜增生。我们建议针对Fn-EDA可以探索为减少新内膜增生的潜在治疗策略。