Pamela Swiatlowska*, Brian Sit*, Zhen Feng*, Emilie Marhuenda, Ioannis Xanthis, Simona Zingaro, Matthew Ward, Xinmiao Zhou, Qingzhong Xiao, Cathy Shanahan, Gareth E Jones, Cheng-han Yu and Thomas Iskratsch
Vascular smooth muscle cells (VSMCs) play a central role in the progression of atherosclerosis, where they switch from a contractile to a synthetic phenotype. Because of their role as risk factors for atherosclerosis, we sought here to systematically study the impact of matrix stiffness and (haemodynamic) pressure on VSMCs. Thereby we find that pressure and stiffness individually affect the VSMC phenotype. However, only the combination of hypertensive pressure and matrix compliance, and as such mechanical stimuli that are prevalent during atherosclerosis, lead to a full phenotypic switch including the formation of matrix degrading podosomes. We further analyse the molecular mechanism in stiffness and pressure sensing and identify a regulation through different, but overlapping pathways, culminating in the regulation of the actin cytoskeleton through cofilin. Altogether, our data shows how different pathological mechanical signals combined, but through distinct pathways accelerate a phenotypic switch that will ultimately contribute to atherosclerotic disease progression.