The combination of hypertensive pressure and matrix compliance leads to a full phenotypic switch of vascular smooth muscle cells, including the formation of matrix-degrading podosomes.
Does the combination of hypertensive pressure and matrix stiffness induce a phenotypic switch in vascular smooth muscle cells?
The combination of hypertensive pressure and matrix stiffness accelerates a phenotypic switch in vascular smooth muscle cells via distinct but overlapping pathways, contributing to atherosclerotic disease progression.
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 (hemodynamic) 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, leads to a full phenotypic switch including the formation of matrix-degrading podosomes. We further analyze 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. Together, our data show how different pathological mechanical signals combined but through distinct pathways accelerate a phenotypic switch that will ultimately contribute to atherosclerotic disease progression.
Swiatlowska et al. (Fri,) conducted a other in Atherosclerosis. Matrix stiffness and hemodynamic pressure was evaluated on Vascular smooth muscle cell phenotype switch and podosome formation. The combination of hypertensive pressure and matrix compliance leads to a full phenotypic switch of vascular smooth muscle cells, including the formation of matrix-degrading podosomes.