Pressure and stiffness sensing together regulate vascular smooth muscle cell phenotype switching

Abstract

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.

Hypertensive Pressure Mechanosensing Alone Triggers Lipid Droplet Accumulation and Transdifferentiation of Vascular Smooth Muscle Cells to Foam Cells

“…[63,64] Along with the Piezo1/pressure-dependent downregulation of H3K9me3 that effectively results in decreased levels of heterochromatin, we also observed reduced Young's modulus, measured just above the nucleus after Yoda1 treatment (reported here) or pressure stimulation (reported previously). [15] These results are in line with the dogma that chromatin compactness is one of the components contributing to the overall nuclear stiffness. [65] The atherosclerotic environment is characterized by altered mechanical properties.…”

“…Tissue Sections: 8-week old male mice were subjected to a complete left common carotid artery (LCCA) ligation as described previously. [15] 28 days after the procedure, the arteries were collected, 2 mm of proximal as well as distal parts were removed and 4-5 mm LCCA was embedded for obtaining 10 μm thick cryosections on the cryostat microtome (Leica Biosystems).…”

Vascular Smooth Muscle Cells Phenotypic Switching in Cardiovascular Diseases

“…The impact of wall pressure on endothelial cells is well documented, whereas the impact of overlapping normal or pathological physical stressors on the intimal VSMCs is less well studied. The mix of hypertensive pressure and matrix adherence, as well as the prevalence of mechanical stimuli during atherosclerosis, leads to an intact VSMCs phenotype transition [ 35 ], according to Pamela Swiatlowska et al…”

Adaptation of Vascular Smooth Muscle Cell to Degradable Metal Stent Implantation

“…Many physical factors, such as blood flow shear stress, stent surface structure, and stent stiffness, influence the proliferation, migration, and phenotypic transformation of VSMCs. ,,, The cytoskeletal distribution and topology beneath VSMCs determine their physiological morphology. VSMCs bear external mechanical forces from blood flow and pressure and readily respond to any mechanical change due to the existence of stents, which redirect fluid flow shear stress (FFSS) and adjust the flow rate and pressure.…”