The influence of microenvironment stiffness on endothelial cell fate: Implication for occurrence and progression of atherosclerosis

Atherosclerosis, the primary cause of cardiovascular diseases (CVDs), is characterized by phenotypic changes in fibrous proliferation, chronic inflammation and lipid accumulation mediated by vascular endothelial cells (ECs) and vascular smooth muscle cells (SMCs) which are correlated with the stiffening and ectopic remodeling of local extracellular matrix (ECM). The native residents, ECs and SMCs, are not only affected by various chemical factors including inflammatory mediators and chemokines, but also by a range of physical stimuli, such as shear stress and ECM stiffness, presented in the microenvironmental niche. Especially, ECs, as a semi-selective barrier, can sense mechanical forces, respond quickly to changes in mechanical loading and provide context-specific adaptive responses to restore homeostasis. However, blood arteries undergo stiffening and lose their elasticity with age. Reports have shown that the ECM stiffening could influence EC fate by changing the cell adhesion, spreading, proliferation, cell to cell contact, migration and even communication with SMCs. The cell behaviour changes mediated by ECM stiffening are dependent on the activation of a signaling cascade of mechanoperception and mechanotransduction. Although the substantial evidence directly indicates the importance of ECM stiffening on the native ECs, the understanding about this complex interplay is still largely limited. In this review, we systematically summarize the roles of ECM stiffening on the behaviours of endothelial cells and elucidate the underlying details in biological mechanism, aiming to provide the process of how ECs integrate ECM mechanics and the highlights for bioaffinity of tissue-specific engineered scaffolds.

Automated summary

Atherosclerosis, characterized by phenotypic changes in fibrous proliferation, chronic inflammation, and lipid accumulation, is the main cause of cardiovascular diseases. This disease is mediated by vascular endothelial cells (ECs) and vascular smooth muscle cells (SMCs) and is correlated with the stiffening and remodeling of local extracellular matrix (ECM). ECM stiffening can influence EC fate by changing cell behavior, such as adhesion, proliferation, and communication with SMCs. Despite substantial evidence, our understanding of this complex interplay is still limited.