{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Jain M"],"funding":["American Heart Association","NHLBI, NIH","NINDS, NIH","NHLBI NIH HHS","NINDS NIH HHS","Leducq foundation Transatlantic Networks of Excellence grant"],"pagination":["295-314"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6934199"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["130(1)"],"pubmed_abstract":["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."],"journal":["The Journal of clinical investigation"],"pubmed_title":["Smooth muscle cell-specific fibronectin-EDA mediates phenotypic switching and neointimal hyperplasia."],"pmcid":["PMC6934199"],"funding_grant_id":["R01 NS109910","18CVD02","18EIA33900009","R35 HL139926","R01NS109910","R35HL139926"],"pubmed_authors":["Cornelissen A","Guo L","Doddapattar P","Finn AV","Nayak MK","Jain M","Chorawala MR","Lentz SR","Dhanesha N","Chauhan AK"],"additional_accession":[]},"is_claimable":false,"name":"Smooth muscle cell-specific fibronectin-EDA mediates phenotypic switching and neointimal hyperplasia.","description":"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.","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Jan","modification":"2025-04-04T22:45:09.532Z","creation":"2025-04-04T22:45:09.532Z"},"accession":"S-EPMC6934199","cross_references":{"pubmed":["31763999"],"doi":["10.1172/JCI124708","10.1172/jci124708"]}}