The classical estrogen receptor ERalpha mediates many of the known cardiovascular effects of estrogen and is expressed in male and female vascular cells. Estrogen-independent activation of ERalpha is known to occur in cells from reproductive tissues, but has not been investigated previously in vascular cells. In this study, transient transfection assays in human saphenous vein smooth muscle cells (HSVSMC) and pulmonary vein endothelial cells (PVEC) demonstrated ERalpha-dependent activation of estrogen response element-based, and vascular endothelial growth factor-based reporter plasmids by both estrogen-deficient FBS (ED-FBS) and EGF. In nonvascular cells, ERalpha-mediated gene expression can be activated via mitogen-activated protein (MAP) kinase- induced phosphorylation of serine 118 of ERalpha. However, in vascular cells, we found that pharmacologic inhibition of MAP kinase did not alter EGF-mediated ERalpha activation. In addition, a mutant ER containing an alanine-for-serine substitution at position 118 was activated to the same degree as the wild-type receptor by ED-FBS and EGF in both HSVSMC and PVEC. Furthermore, constitutively active MAP kinase kinase (MAPKK) activated ERalpha in Cos1 cells as expected, but MAPKK inhibited ER activation in PVEC. We conclude that growth factors also stimulate ERalpha-mediated gene expression in vascular cells, but find that this occurs via a MAP kinase-independent pathway distinct from that reported previously in nonvascular cells.
R H Karas, E A Gauer, H E Bieber, W E Baur, M E Mendelsohn
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