Responses of vascular smooth muscle cells to estrogen are dependent on balance between ERK and p38 MAPK pathway activities

ObjectiveTo investigate the mechanisms underlying the dual effects of estrogen on vascular smooth muscle cells (VSMC).MethodsMTT assay, ELISA, flow cytometry and Western analysis were used to investigate the effects of 17β-estradiol (E2) on proliferation, apoptosis, cell cycle progression, ERK and p38 activities of subcultured rat VSMC with or without chemical block of MEK or p38 kinases.ResultsE2-promoted VSMC proliferation was accompanied with an increased phosphorylation of ERK1/2, which could be blocked by MEK inhibitor U0126; the E2-induced VSMC apoptosis, which appeared mainly in the G2/M phase, was related with the activation of p38 and could be blocked by p38 inhibitor SB203580. More interestingly, MEK inhibition in E2-treated VSMC led to an enhanced p38 phosphorylation and a shift of apoptosis from G2/M phase-predominant to G0/G1 phase-predominant; whereas block of p38 increased the E2-induced ERK1/2 phosphorylation and proliferation of the VSMC. This reciprocal phenomenon was related with cross-talk between ERK and p38 pathways which might be mediated by MKP-1 and PP2A. The effects of E2 on proliferation and apoptosis, and their related pathways could be separately induced by the specific agonists of estrogen receptor (ER) α and β alone and inhibited or eliminated by the ER blocker ICI 182,780.ConclusionThe dual effects of estrogen on VSMC involve concurrent activations of ERK and p38 pathways by ER α and β respectively, and the fates of VSMC are determined by the dynamic balance between these two pathways.