Integrin α9 regulates smooth muscle cell phenotype switching and vascular remodeling

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.

Automated summary

The expression of integrin alpha 9 in human coronary smooth muscle cells (SMCs) affects cell synthetic phenotype, proliferation, and migration, with deficiency leading to decreased cellular activities. Inhibiting integrin alpha 9 can reduce SMC proliferation and migration after vascular injury, suggesting its potential therapeutic application in vascular remodeling.