Rapid effects of aldosterone on clonal human vascular smooth muscle cells.
It has been increasingly appreciated that aldosterone elicits acute vascular effects through nongenomic signaling pathways. Our previous studies demonstrated that aldosterone attenuated phenylephrine-mediated constriction in intact vessels [via phosphatidylinositol 3-kinase-dependent nitric oxide synthase activation] but enhanced vasoconstrictor responses in endothelium-denuded arteries. To determine the mechanism of this vasoconstrictor response, we assessed the effect of aldosterone on myosin light-chain phosphorylation and contraction in clonal adult human vascular smooth muscle cells. Acute aldosterone exposure mediated dose-dependent myosin light-chain phosphorylation, inhibited by spironolactone and phosphatidylinositol 3-kinase inhibition. These rapid effects of aldosterone were mimicked by estradiol and hydrocortisone and were also inhibitable by both spironolactone and eplerenone. In parallel to its effects on myosin light-chain phosphorylation, aldosterone mediated dose-dependent contraction responses that were inhibited by spironolactone. Comparable contractile responses were seen with both 17beta-estradiol and hydrocortisone. In total, these data are consistent with a mechanism of acute aldosterone-mediated contraction common to both glucocorticoids and estrogen. Steroid-mediated vasoconstriction may represent an important pathobiological mechanism of vascular disease, especially in the setting of preexisting endothelial dysfunction.
Gros
Robert
R
Robarts Research Institute, 100 Perth Dr, London, ON, Canada.
Ding
Qingming
Q
Armstrong
Souzan
S
O'Neil
Caroline
C
Pickering
J Geoffrey
JG
Feldman
Ross D
RD
D000450:Aldosterone / Q000494:pharmacology / Q000502:physiology*; D001013:Aorta, Thoracic / Q000166:cytology; D002460:Cell Line; D002999:Clone Cells; D000077545:Eplerenone; D004958:Estradiol; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology*; D018994:Myosin Light Chains / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D018994:Myosin Light Chains; D014662:Vasoconstrictor Agents; D013148:Spironolactone; D000450:Aldosterone; D004958:Estradiol; D000077545:Eplerenone; D019869:Phosphatidylinositol 3-Kinases; D006854:Hydrocortisone