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1 Klinik III fuer Innere Medizin, Universitaet zu Koeln, Koln, Germany
2 Klinik III fuer Innere Medizin, Universitaet zu Koeln, Koln, Germany; Center for Molecular Medicine, University of Cologne (CMMC), Koln, Germany
* To whom correspondence should be addressed. E-mail: stephan.rosenkranz{at}medizin.uni-koeln.de.
Estrogens are known to display significant vasoprotective effects in pre-menopausal women. Platelet-Derived Growth Factor (PDGF) is an important mediator of vascular smooth muscle cell (VSMC) migration and proliferation, and thus atherogenesis. We analyzed the effects of 17-
-estradiol (E2) on PDGF receptor (PDGFR) expression/activation, PDGF-dependent VSMC proliferation, migration and downstream signaling events.
Pretreatment of VSMCs with E2 (0.3µM-0.1mM) for 24 h concentration-dependently inhibited PDGF-induced proliferation and migration up to 85.5±15.8% and 79.4±9.8%, respectively (both p<0.05). These effects were prevented by co-incubation with the estrogen receptor antagonist ICI 182.780. E2 did not alter PDGFR expression, nor did it impair the ligand-induced tyrosine-phosphorylation of the PDGFR and consecutive binding of the receptor-associated signaling molecules SHP-2, PLC
, PI3K, and RasGAP. Thus, estrogens inhibited PDGF-induced cellular responses at the post-receptor level. While stimulation of VSMCs with PDGF-BB led to a transient increase of rac-1 activity, pretreatment with E2 for 24 hours concentration-dependently inhibited PDGF-induced rac-1 activation. Furthermore, inhibition of rac-1 by Clostridium sordellii lethal toxin or overexpression of dominant-negative rac-1 (N17) significantly inhibited PDGF-induced VSMC migration, indicating that rac-1 activity is essential for PDGF-dependent cellular responses. E2 did not further reduce PDGF-induced migration in rac-N17 overexpressing cells, suggesting that it diminishes VSMC migration by altering rac-1 activity.
We conclude that E2 attenuates PDGF-dependent cellular functions of VSMCs downstream of the PDGFR via inhibition of rac-1. These observations offer a molecular explanation for the vasoprotective effects of estrogens.
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