Rapid vascular effects of steroids - a question of balance?

Steroid hormones such as aldosterone and estrogens have been increasingly appreciated as important physiological and pathophysiological regulators of cardiovascular functions. These actions are mediated in part by their 'traditional' steroid receptors - such as estrogen and mineralocorticoid receptors - via well-described transcriptional mechanisms. However, many of the effects of steroids occur over a time course not explained by these longer-term transcriptional mechanisms. These more rapid actions have been shown to have important effects on vascular reactivity and a wide range of second messengers and enzymes. Elucidating the mechanisms and biological impact of these rapid steroid effects has been confounded by our lack of appreciation of the cell types on which these steroids were mediating their rapid effects, and the receptor(s) with which they were interacting. Emerging insights from studies of the rapid vascular effects of both aldosterone and estradiol are helping to clarify these mechanisms. For aldosterone, its rapid effects on vascular reactivity have been variably described as vasodilator, vasoconstrictor or nonexistent. Recent studies have indicated that the net effect of aldosterone on vascular reactivity is dependent on its opposing actions, mediating vasodilation via an endothelial-dependent mechanism and/or vasoconstriction via a direct smooth muscle effect. Both of these mechanisms appear to be phosphoinositide-3 kinase dependent. Thus, appreciating the rapid vascular effects of aldosterone on a given vascular bed is likely to be dependent on appreciating the relative contribution of its endothelial versus its direct vascular smooth muscle effects. Furthermore, a shift in this balance of endothelial to vascular smooth muscle-mediated effects may be important in vascular dysregulation in hypertension and atherosclerotic disease. Studies elucidating the rapid vascular effects of estrogen on the mitogen-activated protein kinase (MAP), extracellular signal-regulated kinase (ERK) and its consequent effects on apoptosis have helped us understand the concept that the variability in directionality of rapid steroid responses may, in part, be related to their interactions with receptor systems mediating opposing effects. For estradiol, we have shown rapid effects via classical estrogen receptors inhibiting ERK activation and, consequently, apoptosis. In contrast, expression G protein-coupled receptor 30 (GPR30), a recently appreciated G protein-coupled receptor implicated in mediating the rapid cellular effects of estrogen, mediates diametrically opposed effects - stimulation of ERK and proapoptotic effects. A shift in the balance of estrogen receptor versus GPR30 regulation with aging, hypertension and/or atherosclerotic disease might critically shift the balance of beneficial versus harmful effects of estrogen on the vasculature.