title: Delineating the receptor mechanisms underlying the rapid vascular contractile effects of aldosterone and estradiol.
abstract: It is increasingly appreciated that steroid hormones such as aldosterone and estradiol can mediate important cardiovascular effects. Many of these effects occur over a time course not consistent with the genomic actions of these hormones acting through classical nuclear receptors / transcription factors. Further, multiple receptors have been implicated in mediating these rapid effects of both aldosterone and estradiol, including a newly appreciated G-protein-coupled receptor, GPR30. In previous studies we demonstrated that both aldosterone and estradiol mediate contraction in vascular smooth muscle cells, as assessed in single cell assays. However, the receptor mechanisms underlying these effects remained unclear. Therefore, we studied the actions of estradiol and aldosterone on rat aortic vascular smooth muscle cells. Both aldosterone and estradiol mediated a concentration-dependent increase in contraction, as assessed in substrate deformation assays with EC(50)s in the range of nanomoles per litre. These effects paralleled increased myosin light chain phosphorylation. The effects of aldosterone were inhibited by the mineralocorticoid selective antagonist eplerenone. Further, aldosterone's contractile effects were enhanced by increased expression of the mineralocorticoid receptor. The contractile effects of estradiol were inhibited by estrogen receptor (ER)-selective antagonists, tamoxifen, and ICI 182780, as well as eplerenone. Further, estradiol's effects were enhanced by the increased expression of both ERα and the mineralocorticoid receptor (MR). To assess the potential role of GPR30 in mediating the effects of aldosterone and estradiol, GPR30 was re-introduced, since these cells lose endogenous GPR30 expression in culture. Re-expression of GPR30 enhanced both estradiol- and aldosterone-mediated contraction. These studies demonstrate that in rat aortic vascular smooth muscle cells, both aldosterone and estradiol mediate vascular smooth muscle contraction and that these effects can be mediated by MR, ERα, and by GPR30.
authors.affiliation: Vascular Biology Research Groups, Robarts Research Institute, London, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Gros
authors.forename: Qingming
authors.initials: Q
authors.lastname: Ding
authors.forename: Mark
authors.initials: M
authors.lastname: Davis
authors.forename: Rasha
authors.initials: R
authors.lastname: Shaikh
authors.forename: Bonan
authors.initials: B
authors.lastname: Liu
authors.forename: Jozef
authors.initials: J
authors.lastname: Chorazyczewski
authors.forename: J Geoffrey
authors.initials: JG
authors.lastname: Pickering
authors.forename: Ross D
authors.initials: RD
authors.lastname: Feldman
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D000077545:Eplerenone; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011921:Rats, Inbred WKY; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects* / Q000235:genetics
chemical_list: D047628:Estrogen Receptor alpha; D018994:Myosin Light Chains; D043562:Receptors, G-Protein-Coupled; D018161:Receptors, Mineralocorticoid; D013629:Tamoxifen; D013148:Spironolactone; D000450:Aldosterone; D004958:Estradiol; D000077545:Eplerenone