TY - JOUR AU - Jain, Manish AU - Dhanesha, Nirav AU - Doddapattar, Prakash AU - Chorawala, Mehul R. AU - Nayak, Manasa K. AU - Cornelissen, Anne AU - Guo, Liang AU - Finn, Aloke V. AU - Lentz, Steven R. AU - Chauhan, Anil K. T1 - Smooth muscle cell–specific fibronectin-EDA mediates phenotypic switching and neointimal hyperplasia PY - 2020/01/02/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI124708 VL - 130 IS - 1 UR - https://doi.org/10.1172/JCI124708 SP - 295 EP - 314 PB - The American Society for Clinical Investigation ER -