Substrate stiffness differentially impacts autophagy of endothelial cells and smooth muscle cells

Stiffening of blood vessels is one of the most important characteristics in the process of many cardiovascular pathologies such as atherosclerosis, angiosteosis, and vascular aging. Increased stiffness of the vascular extracellular matrix drives artery pathology and alters phenotypes of vascular cell. Understanding how substrate stiffness impacts vascular cell behaviors is of great importance to the biomaterial design in tissue engineering, regenerative medicine, and medical devices. Here we report that changing substrate stiffness has a significant impact on the autophagy of vascular endothelial cells (VECs) and smooth muscle cells (VSMCs). Interestingly, our findings demonstrate that, with the increase of substrate stiffness, the autophagy level of VECs and VSMCs showed differential changes: endothelial autophagy levels reduced, leading to the reductions in a range of gene expression associated with endothelial function; while, autophagy levels of VSMCs increased, showing a transition from contractile to the synthetic phenotype. We further demonstrate that, by inhibiting cell autophagy, the expressions of endothelial functional gene were further reduced and the expression of VSMC calponin increased, suggesting an important role of autophagy in response of the cells to the challenge of microenvironment stiffness changing. Although the underlying mechanism requires further study, this work highlights the relationship of substrate stiffness, autophagy, and vascular cell behaviors, and enlightening the design principles of surface stiffness of biomaterials in cardiovascular practical applications.

Automated summary

The stiffness of the vascular extracellular matrix plays a crucial role in artery pathology and can impact the autophagy levels of vascular endothelial cells and smooth muscle cells. Increasing substrate stiffness leads to differential changes in autophagy levels, affecting gene expression associated with endothelial function and transitioning VSMCs from contractile to synthetic phenotype. Inhibiting cell autophagy further reduces endothelial functional gene expression and increases VSMC calponin expression, highlighting the important role of autophagy in response to changes in microenvironment stiffness.