Tropomodulin1 regulates the biomechanical changes in macrophages induced by matrix stiffness.

The monocyte/macrophage infiltration plays critical roles in the development of atherosclerosis. Arterial stiffness is a cholesterol-independent risk factor for cardiovascular events. The regulation of arterial stiffness on biomechanics of macrophages and its underlying mechanism remains unclear. We prepared polyacrylamide gels with low and high stiffness that corresponded to healthy and diseased blood vessels, respectively. We found that macrophages cultured on stiff matrix had increased rigidity and migration ability compared to those on soft matrix. An actin capping protein, tropomodulin1 (Tmod1) was upregulated in macrophages by stiff matrix and in arteries with high stiffness. Further analyses showed that deficiency of Tmod1 in macrophages completely or partially prevented the changes in actin polymerization, cell adhesion and cell spreading induced by stiff matrix. Overexpression of Tmod1 in macrophages enhanced actin polymerization, cell adhesion and spreading on stiff matrix. Tmod1 was involved in the regulation of vinculin expression and formation of focal adhesion in macrophages on stiff matrix. Finally, the deficiency of Tmod1 in macrophages retarded the formation of atherosclerotic plaques in blood vessels with high matrix stiffness. The results suggest that Tmod1 was a key regulator in macrophage rigidity and migration on stiff substrate. The present work will help us to understand the biomechanical mechanisms for the development of atherosclerosis.