Dehydroepiandrosterone Activates Endothelial Cell Nitric-oxide Synthase by a Specific Plasma Membrane Receptor Coupled to Gαi2,3

Abstract

The adrenal steroid dehydroepiandrosterone (DHEA) has no known cellular receptor or unifying mechanism of action, despite evidence suggesting beneficial vascular effects in humans. Based on previous data from our laboratory, we hypothesized that DHEA binds to specific cell-surface receptors to activate intracellular Gproteins and endothelial nitric-oxide synthase (eNOS). We now pharmacologically characterize a putative plasma membrane DHEA receptor and define its associated G-proteins. The physiological role of the adrenal steroid dehydroepiandrosterone (DHEA) 1 is not known. There are widespread data suggesting a beneficial effect of DHEA on vascular function. Extensive epidemiologic evidence shows an inverse correlation between circulating DHEA levels and the prevalence of atherosclerotic and cardiovascular diseases (1-5). There are few human intervention studies focused on vascular outcomes of DHEA administration, and these are not of a size or duration to define whether DHEA therapy has an effect on cardiovascular morbidity or mortality. Available studies do suggest a beneficial effect on atherosclerosis (6). Studies of the short term effect of DHEA on human vascular function, using sophisticated assays of vascular function, are beginning to emerge. Williams et al. (7) showed a significant increase in flow-mediated dilatation and systemic arterial compliance in postmenopausal women taking DHEA for 3 months. DHEA reduces atherosclerosis, decreases the accumulation of cholesterol in aortic and coronary arteries (8, 9), and inhibits platelet aggregation (10) in various animal models. DHEA also affects growth factor-induced mitogenesis and proliferation of vascular smooth muscle cells (11-13). However, the molecular mechanisms by which DHEA acts to protect from atherosclerotic and cardiovascular diseases are still unknown. Furthermore, it is unclear whether the effect on vascular tissues is related to DHEA or to its metabolites, which include estradiol.Steroid hormones are known to bind specific intracellular receptors, which function as ligand-dependent gene transcription factors (14). However, previous efforts to isolate an intracellular receptor for DHEA have failed (15-18). In contrast to this classical pathway of steroid hormone action, there are also rapid, plasma membrane-dependent, non-genomic effects of steroids in various tissues, which lead to important physiological responses (19 -24). Plasma membrane-associated receptors are postulated to mediate these non-genomic actions of steroids. Functional plasma membrane binding sites have been identified for several steroids, including estrogen, vitamin D, and progesterone (25-28). However, besides the receptor for estrogen, no plasma membrane steroid receptor has yet been unequivocally identified and characterized.We have found that DHEA stimulates nitric oxide (NO) generation within minutes from bovine aortic endothelial cells (BAEC).2 Furthermore, DHEA conjugated to bovine serum albumin (BSA) had similar effects. These cellular responses to DHEA were spe...

Testosterone and Erectile Function: From Basic Research to a New Clinical Paradigm for Managing Men with Androgen Insufficiency and Erectile Dysfunction

“…DHEA use may be justified in aging men with periodic evaluations to maintain serum concentrations in the physiologic range [149]. Recent evidence suggests that DHEA has a physiologic role through interaction with specific membrane receptors on the endothelium [150].…”

Androgen in postmenopausal women

“…DHEA and DHEA-S were considered to be pro-hormones exerting indirect androgenic and estrogenic effects following peripheral conversion into small amounts Group A : early reproductive stage, Group B : late reproductive stage, Group C : early menopausal transition, Group D : late menopausal transition, Group E : women for whom less than 1 year has passed since menopause, Group F : women for whom less than 5 years have passed since menopause, Group G : women for whom more than 5 years have passed since menopause of testosterone and estradiol. However, this concept may change due to the identification of a putative specific DHEA receptor on the plasma membrane of bovine aortic endothelial cells (12).…”

Serum Dehydroepiandrosterone Sulphate Levels in Patients with Non-Alcoholic Fatty Liver Disease

“…Some effects of DHEA are not exactly the same as those of androgens, and thus the presence of DHEA receptors different from classical steroid receptors is postulated. High-affinity binding sites of DHEA have been shown in T lymphocytes, liver, vascular endothelial cells, adrenal medulla cells, which are thought to present in membrane fractions (30,31). At present, there is no data implying a molecular mechanism as to the relation of DHEAS with NAFLD.…”