Journal article
Integrin alpha 9 regulates smooth muscle cell phenotype switching and vascular remodeling
JCI insight, Vol.6(10), e147134
05/24/2021
DOI: 10.1172/jci.insight.147134
PMCID: PMC8262341
PMID: 34027892
Abstract
Excessive proliferation of vascular smooth muscle cells (SMCs) remains a significant cause of in-stent restenosis. Integrins, which are heterodimeric transmembrane receptors, play a crucial role in SMC biology by binding to the extracellular matrix protein with the actin cytoskeleton within the SMC. Integrin alpha 9 plays an important role in cell motility and autoimmune diseases; however, its role in SMC biology and remodeling remains unclear. Herein, we demonstrate that stimulated human coronary SMCs upregulate alpha 9 expression. Targeting alpha 9 in stimulated human coronary SMCs, using anti-integrin alpha 9 antibody, suppresses synthetic phenotype and inhibits SMC proliferation and migration. To provide definitive evidence, we generated an SMC-specific alpha 9-deficient mouse strain. Genetic ablation of alpha 9 in SMCs suppressed synthetic phenotype and reduced proliferation and migration in vitro. Mechanistically, suppressed synthetic phenotype and reduced proliferation were associated with decreased focal adhesion kinase/steroid receptor coactivator signaling and downstream targets, including phosphorylated ERK, p38 MAPK, glycogen synthase kinase 3 beta, and nuclear beta-catenin, with reduced transcriptional activation of beta-catenin target genes. Following vascular injury, SMC-specific alpha 9-deficient mice or wild-type mice treated with murine anti-integrin alpha 9 antibody exhibited reduced injury-induced neointimal hyperplasia at day 28 by limiting SMC migration and proliferation. Our findings suggest that integrin alpha 9 regulates SMC biology, suggesting its potential therapeutic application in vascular remodeling.
Details
- Title: Subtitle
- Integrin alpha 9 regulates smooth muscle cell phenotype switching and vascular remodeling
- Creators
- Manish Jain - Roy J. and Lucille A. Carver College of MedicineRishabh Dev - University of IowaPrakash Doddapattar - Roy J. and Lucille A. Carver College of MedicineShigeyuki Kon - Fukuyama UniversityNirav Dhanesha - University of IowaAnil K. Chauhan - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.6(10), e147134
- DOI
- 10.1172/jci.insight.147134
- PMID
- 34027892
- PMCID
- PMC8262341
- NLM abbreviation
- JCI Insight
- eISSN
- 2379-3708
- Publisher
- Amer Soc Clinical Investigation Inc
- Number of pages
- 18
- Grant note
- R35HL139926; R01NS109910; U01NS113388 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 18EIA33900009 / Established Investigator Award from American Heart Association
- Language
- English
- Date published
- 05/24/2021
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359837702771
Metrics
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