17Beta-estradiol attenuates PDGF signaling in vascular smooth muscle cells at the postreceptor level.
Estrogens are known to display significant vasoprotective effects in premenopausal women. PDGF is an important mediator of vascular smooth muscle cell (VSMC) migration and proliferation, and thus atherogenesis. We analyzed the effects of 17beta-estradiol (E2) on beta-PDGF receptor (beta-PDGFR) expression/activation and PDGF-dependent VSMC proliferation, migration, and downstream signaling events. Pretreatment of VSMCs with E2 (0.3 microM-0.1 mM) 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 coincubation with the ER antagonist ICI-182780. E2 did not alter beta-PDGFR expression, nor did it impair the ligand-induced tyrosine phosphorylation of the beta-PDGFR and consecutive binding of the receptor-associated signaling molecules Src homology region 2-containing phosphatase-2, PLC-gamma, phosphatidylinositol 3-kinase, and RasGAP. Thus estrogens inhibited PDGF-induced cellular responses at the postreceptor level. Although stimulation of VSMCs with PDGF-BB led to a transient increase of rac-1 activity, pretreatment with E2 for 24 h 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 (rac-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 beta-PDGFR via inhibition of rac-1. These observations offer a molecular explanation for the vasoprotective effects of estrogens.
Kappert
Kai
K
Klinik III für Innere Medizin der Universität zu Köln, Kerpener Str. 62, 50924 Köln, Germany.
Caglayan
Evren
E
Huntgeburth
Michael
M
Bäumer
Anselm T
AT
Sparwel
Jan
J
Uebel
Manuela
M
Rosenkranz
Stephan
S
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism / Q000502:physiology
D010982:Platelet-Derived Growth Factor; D011960:Receptors, Estrogen; D004958:Estradiol; D020797:Receptor, Platelet-Derived Growth Factor beta; D020830:rac1 GTP-Binding Protein