Matrix stiffness regulates the interactions between endothelial cells and monocytes

Endothelial cells (ECs) serve as a barrier between circulating blood and the blood vessel wall. The recruitment and adhesion of monocytes to ECs play a critical role in the initiation of vascular diseases such as atherosclerosis. The functions of ECs are not only regulated by biochemical factors but also hemodynamic forces and matrix stiffness. The deposition of lipids and cholesterol in intima and the aging process may result in the change of stiffness in blood vessels. However, how matrix stiffness influences EC-monocyte interactions is not well understood. Here we investigated the effects of matrix stiffness on the chemotactic migration and adhesion of monocytes to ECs. ECs cultured on either soft (8 kPa) matrix or stiff (40 kPa) matrix had more chemotactic effect on monocytes compared to those on 20 kPa matrix. Moreover, monocyte adhesion exhibited a similar pattern, which was correlated with the expression levels of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1). Interestingly, miR-126 and miR-222 showed a reverse expression pattern of VCAM-1 and ICAM-1 respectively. By inhibiting miR-126 and miR-222, the effect of matrix stiffness on monocyte adhesion was abolished, suggesting that the expression of miR-126 (targeting VCAM-1) and miR-222 (targeting ICAM-1) mediated the stiffness effect on the expression of VCAM-1 and ICAM-1. These findings shed lights on how matrix stiffness regulates the interactions of ECs and monocytes and advance our understanding on the pathogenesis of atherosclerosis and aging. This work provides a rational basis for vascular tissue engineering, disease modeling and therapeutic development.