Hormonal modulation of endothelial NO production

Abstract

Since the discovery of endothelium-derived relaxing factor and the subsequent identification of nitric oxide (NO) as the primary mediator of endothelium-dependent relaxations, research has focused on chemical and physical stimuli that modulate NO levels. Hormones represent a class of soluble, widely circulating chemical factors that impact production of NO both by rapid effects on the activity of endothelial nitric oxide synthase (eNOS) through phosphorylation of the enzyme and longer term modulation through changes in amount of eNOS protein. Hormones that increase NO production including estrogen, progesterone, insulin, and growth hormone do so through both of these common mechanisms. In contrast, some hormones, including glucocorticoids, progesterone, and prolactin, decrease NO bioavailability. Mechanisms involved include binding to repressor response elements on the eNOS gene, competing for co-regulators common to hormones with positive genomic actions, regulating eNOS co-factors, decreasing substrate for eNOS, and increasing production of oxygen-derived free radicals. Feedback regulation by the hormones themselves as well as the ability of NO to regulate hormonal release provides a second level of complexity that can also contribute to changes in NO levels. These effects on eNOS and changes in NO production may contribute to variability in risk factors, presentation of and treatment for cardiovascular disease associated with aging, pregnancy, stress, and metabolic disorders in men and women.

Figures

Fig. 1

Effect of estrogen (E2) on endothelial nitric oxide synthase (eNOS). E2 binds to estrogen receptors α or β (ERα/β) in two locations: membrane-associated or cytosolic. As discussed in the text, binding of E2 to the membrane-associated form activates the phosphoinositide-3-kinase/protein kinase B (PI3 K/AkT) pathway leading to phosphorylation of eNOS at serine 1177. This increases eNOS activity and production of NO. Binding of E2 to cytosolic ERα/β leads to translocation of the bound receptor into the nucleus. There the liganded receptor binds to co-regulators and DNA response elements on the eNOS gene to initiate transcription and increase eNOS mRNA production. mRNA is then translated by the ribosome to increase eNOS protein production

Fig. 2

Schematic illustrating interactions of hormones in regulation of eNOS. Changes in production of NO will represent the culmination of effects of multiple hormones through both non-genomic and genomic mechanisms. Hormones can also affect levels of NO through indirect mechanisms including alterations in enzyme activity through changes in availability of enzyme co-factors and substrate, or changes in bioavailability of NO through production of oxygen-derived free radicals. In addition, production of NO in specific organs, such as the brain or thyroid, also may affect release of gonadotropins, or thyroid hormone, respectively. Neuronal activity, particularly related to stress, can alter release of ACTH and thus, modify release of glucocorticoids from the adrenal gland. Estrogen and testosterone affect neuronal function and activation of NOS in the brain as well as inhibit release of gonadotropins from the pituitary. These integrated actions of hormones on eNOS will vary across the life span with changes in gonadal function associated with puberty, pregnancy, aging, and stress, thus altering the balance among hormones at the level of the endothelial cell