Responses of vascular smooth muscle cells to estrogen are dependent on balance between ERK and p38 MAPK pathway activities.
OBJECTIVE
To investigate the mechanisms underlying the dual effects of estrogen on vascular smooth muscle cells (VSMC).


METHODS
MTT assay, ELISA, flow cytometry and Western analysis were used to investigate the effects of 17beta-estradiol (E(2)) on proliferation, apoptosis, cell cycle progression, ERK and p38 activities of subcultured rat VSMC with or without chemical block of MEK or p38 kinases.


RESULTS
E(2)-promoted VSMC proliferation was accompanied with an increased phosphorylation of ERK1/2, which could be blocked by MEK inhibitor U0126; the E(2)-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 E(2)-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 E(2)-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 E(2) on proliferation and apoptosis, and their related pathways could be separately induced by the specific agonists of estrogen receptor (ER) alpha and beta alone and inhibited or eliminated by the ER blocker ICI 182,780.


CONCLUSIONS
The dual effects of estrogen on VSMC involve concurrent activations of ERK and p38 pathways by ER alpha and beta respectively, and the fates of VSMC are determined by the dynamic balance between these two pathways.
Cheng
Bei
B
Department of Anatomy and Embryology, Wuhan University School of Medicine, PR China.
Song
Jian
J
Zou
Yun
Y
Wang
Qiao
Q
Lei
Yueshan
Y
Zhu
Congli
C
Hu
Chengjun
C
D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004967:Estrogens / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism* / Q000502:physiology; D005260:Female; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology
D004967:Estrogens; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases