title: Aldosterone mediates its rapid effects in vascular endothelial cells through GPER activation.
abstract: The importance of the rapid vascular effects of aldosterone is increasingly appreciated. Through these rapid pathways, aldosterone has been shown to regulate vascular contractility, cell growth, and apoptosis. In our most recent studies, we demonstrated the effects of aldosterone on cell growth and contractility in vascular smooth muscle cells. We showed that these effects could occur via activation of the classic mineralocorticoid receptor, as well the recently characterized G protein-coupled estrogen receptor (GPER), initially characterized as an estrogen-specific receptor. However, the mechanisms underlying aldosterone's endothelium-dependent actions are unknown. Furthermore, the ERK regulatory and proapoptotic effects of aldosterone mediated by GPER activation in cultured vascular smooth muscle cells were only apparent when GPER was reintroduced into these cells by gene transfer. Whether GPER activation via aldosterone might be an important regulator in native vascular cells has been questioned. Therefore, to determine the role of GPER in mediating aldosterone's effects on cell growth and vascular reactivity in native cells, we examined rat aortic vascular endothelial cells, a model characterized by persistent robust expression of GPER, but without detectable mineralocorticoid receptor expression. In these endothelial cells, the GPER agonist G1 mediates a rapid increase in ERK phosphorylation that is wholly GPER-dependent, paralleling the actions of aldosterone. The effects of G1 and aldosterone to stimulate ERK phosphorylation paralleled their proapoptotic and antiproliferative effects. In previous studies, we reported that aldosterone mediates a rapid endothelium-dependent vasodilatory effect, antagonistic to its direct vasoconstrictor effect in endothelium-denuded preparations. Using a rat aortic ring/organ bath preparation to determine the GPER dependence of aldosterone's endothelium-dependent vasodilator effects, we demonstrate that aldosterone inhibits phenylephrine-mediated contraction. This vasodilator effect parallels the actions of the GPER agonist G1. Furthermore, the effects of aldosterone were completely ablated by the GPER antagonist G15. These data support an important role of GPER activation in aldosterone-mediated regulation of endothelial cell growth, as well as in aldosterone's endothelium-mediated regulation of vasoreactivity.
authors.affiliation: Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Gros
authors.forename: Qingming
authors.initials: Q
authors.lastname: Ding
authors.forename: Bonan
authors.initials: B
authors.lastname: Liu
authors.forename: Jozef
authors.initials: J
authors.lastname: Chorazyczewski
authors.forename: Ross D
authors.initials: RD
authors.lastname: Feldman
mesh_terms: D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000502:physiology*; D045462:Endothelium-Dependent Relaxing Factors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018014:Gene Transfer Techniques; D000451:Mineralocorticoid Receptor Antagonists; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014661:Vasoconstriction / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology
chemical_list: D002316:Cardiotonic Agents; D045462:Endothelium-Dependent Relaxing Factors; C520305:Gper1 protein, rat; D000451:Mineralocorticoid Receptor Antagonists; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D018161:Receptors, Mineralocorticoid; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D000450:Aldosterone; D048049:Extracellular Signal-Regulated MAP Kinases