Journal article
Smooth muscle cell-specific fibronectin-EDA mediates phenotypic switching and neointimal hyperplasia
The Journal of clinical investigation, Vol.130(1), pp.295-314
01/01/2020
DOI: 10.1172/JCI124708
PMCID: PMC6934199
PMID: 31763999
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.
Details
- Title: Subtitle
- Smooth muscle cell-specific fibronectin-EDA mediates phenotypic switching and neointimal hyperplasia
- Creators
- Manish Jain - University of IowaNirav Dhanesha - University of IowaPrakash Doddapattar - University of IowaMehul R. Chorawala - University of IowaManasa K. Nayak - University of IowaAnne Cornelissen - CVPath InstituteLiang Guo - CVPath InstituteAloke V. Finn - CVPath InstituteSteven R. Lentz - University of IowaAnil K. Chauhan - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.130(1), pp.295-314
- Publisher
- Amer Soc Clinical Investigation Inc
- DOI
- 10.1172/JCI124708
- PMID
- 31763999
- PMCID
- PMC6934199
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Number of pages
- 20
- Grant note
- CVPath Institute Research Rotation Program of the Medical Faculty of RWTH Aachen University 18EIA33900009 / American Heart Association R35HL139926; R01NS109910 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 18CVD02 / Leducq Foundation Transatlantic Networks of Excellence; Leducq Foundation
- Language
- English
- Date published
- 01/01/2020
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359834602771
Metrics
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