Matrix stiffness and blood pressure together regulate vascular smooth muscle cell phenotype switching and cofilin dependent podosome formation

Vascular smooth muscle cells (VSMCs) play a central role in the onset and progression of atherosclerosis. In pre-atherosclerotic lesions, VSMCs switch from a contractile to a synthetic phenotype and subsequently remodel the microenvironment, leading to further disease progression. Ageing and associated mechanical changes of the extracellular matrix as well as hypertension are major risk of atherosclerosis. Consequently, we sought here to systematically study the impact of mechanical and chemical stimulations on VSMC phenotypic switching. We find that the hemodynamic pressure and matrix stiffness have overlapping effects and together contribute to the phenotypic changes in cellular mechanics, podosome formation, and matrix degradation. We further identify cofilin as a key modulator of the mechanosensitive phenotype switch, which is regulated through Ca2+/slingshot-dependent pressure sensing and RhoA/ROCK-dependent stiffness sensing pathways. Altogether, microenvironment stimulations of high pressure and soft matrix collectively promote the cofilin activity, VSMC migration, and the early progression of atherosclerosis.