How steroid hormones act on the endothelium—insigh

Authors: Uta Hillebrand Martin Hausberg Detlef Lang Christian Stock Christoph Riethmüller Chiara Callies Eckhart Büssemaker

Publish Date: 2008/01/03

Volume: 456, Issue: 1, Pages: 51-60

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Abstract

Vascular actions of steroid hormones have gained increasing importance Indeed some steroid hormones favorably influence vascular structure and function whereas others are detrimental This review will focus on the endothelial effects of steroid hormones In the first part we summarize data from in vivo studies elucidating the regulation of endothelial function by steroid hormones Accumulating data argue for an improvement of endotheliumderived relaxation and impaired vascular contraction by estradiol whereas testosterone progesterone and aldosterone have contrary effects In the second part we present data from novel atomic force microscopy studies performed in living endothelial cells under the influence of steroid hormones These studies provide insight into structural and functional alterations of endothelial cells characterized by changes in volume apical surface and stiffness We summarize the available evidence that changes in shape of endothelial cells translate into changes of endothelial cell stiffness Under the influence of estradiol endothelial cells become spherical with consecutive improvement of elasticity whereas aldosterone flattens endothelial cellshape leading to increased stiffness Both endothelial cell shape and stiffness are major determinants of endothelial nitric oxide production These studies emphasize the great potential of atomic force microscopy to investigate the function of living endothelial cellsResearch over the last two decades has been clearly demonstrating that the vascular endothelium is a target for steroid hormones eg sex hormones glucocorticoids and mineralocorticoids 25 35 Indeed specific receptors for these steroid hormones have been identified in endothelial cells Numerous clinical studies demonstrate that the various steroid hormones affect vascular function in different waysVascular endothelial cells and vascular smooth muscle cells express receptors for estradiol progesterone and testosterone 54 55 66 The sex hormones bind to specific cytosolic receptors The resulting complexes are transported into the nucleus and initiate gene transcription socalled genomic effects Moreover sex hormones cause a number of rapid nongenomic effects on vascular endothelial and smooth muscle cellsSeveral studies report gender differences in vascular function Vascular contraction was found to be greater in male and ovarectomized female rats than in castrated male and female rats suggesting an effect of testosterone in favor of vascular contraction and an effect of estradiol in favor of preventing vascular contraction 24 Specifically estradiol has been shown to cause endotheliummediated vasorelaxation whereas testosterone and progesterone interfere with estradiolmediated endotheliumdependent vasodilation 25There is a body of evidence suggesting that sex hormones interfere with the synthesis and bioavailability of endotheliumderived nitric oxide NO 10 58 Animal studies show that the release of NO from the endothelium is greater in female than in male rats 19 62 Indeed estradiol induces endothelial nitric oxide synthase eNOS expression mediated via the estradiol receptor alpha Moreover estradiol interacts with estradiol receptors in the cell membrane and causes rapid nongenomic signaling pathways that regulate eNOS activity partly by eNOS translocation to the cell membrane In addition to stimulating NO synthesis estradiol has antioxidant effects and inhibits superoxide formation and thereby increases NO bioavailability 41 On the other hand progesterone and testosterone may have some stimulatory effect on NO production but progesterone has been shown to counteract the stimulatory effects on NO release 41 66Moreover sex hormones interact with endotheliumderived contracting factors Estradiol attenuates endothelin 1 ET1 and endothelin beta receptor messenger RNA mRNA expression and inhibits ET1 production in endothelial cells Furthermore progesterone inhibits endothelial ET1 production whereas testosterone stimulates ET1 release from the endothelium 11 66There is substantial evidence that glucocorticoids downregulate eNOS mRNA and protein expression in cultured endothelial cells and also in the isolated vessels 59 Moreover glucocorticoids suppress the production of endotheliumderived vasodilators Glucocorticoid excess causes increased superoxide formation thus increased oxidative stress in endothelial cells 22 However a recent study did not show any change of endotheliummediated vasodilatation with shortterm dexamethasone application in healthy subjects 7 On the other hand in states of inflammation glucocorticoid treatment may improve endothelial function For example in patients with giant cell arteritis steroid treatment was associated with an improvement of brachial artery flowmediated dilatation 15 Interestingly shear stress caused a nuclear localization of the endothelial glucocorticoid receptor similar to that induced by highdose steroid treatment suggesting an antiatherosclerotic effect of glucocorticoids 23 Additionally glucocorticoids reduce endothelial permeability and interfere with the production and action of adhesion molecules For example dexamethasone was shown to reduce cytokineinduced expression of intercellular adhesion molecule 1 ICAM1 and vascular cell adhesion molecule 1 in cultured endothelial cells By contrast sex hormones had no substantial effect on endothelial adhesion molecule expression 9

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