Résumé
Coronary artery disease due to atherosclerosis is the leading cause of death worldwide. Recent studies revealed an important role of smooth muscle cell (SMC) phenotypic switching in atherogenesis. How the extracellular matrix affects SMC phenotype in atherosclerotic lesions is not well understood. Fibronectin (Fn1) is an abundant component of the extracellular matrix in plaques and has been linked to coronary artery disease risk in humans.
We used mouse genetics combined with single-cell analyses, cell lineage tracing, and immunostaining of murine and human atherosclerotic lesions.
Genetic ablation of SMC-derived Fn1 in mice led to a decrease of alpha smooth muscle actin-positive cells in atherosclerotic lesions and a reduced collagen content in the fibrous cap indicative of decreased plaque stability. Plaques lacking SMC-derived Fn1 contained more modulated SMCs with relatively low collagen expression. Interestingly, a subset of the modulated SMCs showed high expression of NO-sensitive guanylyl cyclase (NO-GC). NO-GC is a major cGMP generator in SMCs and like Fn1 has been implicated in coronary artery disease. Fn1 knockout SMCs showed increased cell growth and activity of the NO-cGMP pathway. Expression of Fn1 and NO-GC was also detected in modulated SMCs of human atherosclerotic lesions.
SMC-derived Fn1 promotes plaque stability through suppression of SMC phenotypes with low alpha smooth muscle actin and collagen expression. This atheroprotective effect might be mediated, at least in part, by a crosstalk between Fn1 and the NO-cGMP axis in SMCs. Our study identifies a mechanistic link between 2 coronary artery disease risk genes, Fn1 and NO-GC, which explains how the extracellular matrix regulates SMC phenotype and plaque stability.