Cyclic strain modulates migration and proliferation of vascular smooth muscle cells via Rho-GDIalpha, Rac1, and p38 pathway

Abstract

Cyclic strain is an important inducer of proliferation and migration of vascular smooth muscle cells (VSMCs) which are involved in vascular remodeling during hypertension. However, its mechanism remains to be elucidated. VSMCs of rat aorta were exposed to cyclic strains in vitro with defined parameters, the static, 5%-strain (physiological) and 15%-strain (pathological), at 1.25 Hz for 24 h respectively. Then the possible signaling molecules participated in strain-induced VSMC migration and proliferation were investigated. The results showed that 15%-strain significantly increased VSMC migration and proliferation in comparison with 5%-strain. Expression of Rho GDP dissociation inhibitor alpha (Rho-GDIalpha) was repressed by 15%-strain, but expressions of phospho-Rac1 and phospho-p38 were increased. Expressions of phospho-Akt and phospho-ERK1/2 were similar between the static, 5%-strain and 15%-strain groups. Rho-GDIalpha "knock-down" by target siRNA transfection increased migration and proliferation of VSMCs, and up-regulated phosphorylation of Rac1 and p38 in all groups. Rac1 "knock-down" repressed migration and proliferation of VSMCs, down-regulated phosphorylation of p38, but had no effect on Rho-GDIalpha expression. When siRNAs of Rho-GDIalpha and Rac1 were co-transfected to VSMCs, the expressions of Rho-GDIalpha and phospho-Rac1 were both decreased, and the effects of Rho-GDIalpha "knock-down" were blocked. Rho-GDIalpha "knock-down" promoted while Rac1 "knock-down" postponed the assembly of stress fibers and focal adhesions in static. The results demonstrate that the pathological cyclic strain might induce migration and proliferation of VSMCs via repressing expression of Rho-GDIalpha, which subsequently verified phosphorylations of Rac1 and p38.