Estrogen inhibits mechanical strain-induced mitogenesis in human vascular smooth muscle cells via down-regulation of Sp-1

Objective: The cellular basis of the cardioprotective effects of estrogen a re largely unknown. An inhibitory effect on vascular smooth muscle (VSM) gr owth has been proposed. We examined the effect of 17 beta -estradiol (E2) o n mechanical strain-induced mitogenesis in human fetal VSM cells. Methods a nd results: Cells were grown on fibronectin-coated plates with silicone-ela stomer bottoms, and exposed to cyclic mechanical strain (60 cycles/min), wi th and without E2 (1 nmol/l), for 48 h. [H-3]-Thymidine incorporation was m easured during the last 6 h. Strain induced 1.5-2 fold increases in DNA syn thesis that were attenuated by antibodies to platelet-derived growth factor (PDGF) AA and BB. Strain also induced increases both in mRNA and protein l evels of Sp-1, a transcription factor that binds to the PDGF-A gene promote r site. E2 attenuated strain-induced mitogenesis, and also increases in mRN A and protein levels of Sp-1. The estrogen receptor (ER) antagonist ICI 182 ,780 (100 nmol/l) reversed the inhibitory effect of E2 on strain-induced in creases in DNA synthesis and Sp-1 protein. RT-PCR analysis showed presence of both ER-alpha and -beta in these cells. Conclusions: Estrogen inhibits s train-induced mitogenesis in human VSM cells via an ER mediated process inv olving down-regulation of the transcription factor Sp-1. (C) 2001 Elsevier Science B.V. All rights reserved.