Gender, Estrogen, and NOS

Abstract

Evidence from observational studies as well as prospective randomized trials indicates that the incidence of coronary artery disease is less in premenopausal women compared with age-matched men and in postmenopausal women who are using estrogen replacement therapy. 1,2 The mechanisms by which estrogen reduces development of cardiovascular disease are multifactorial and, in addition to alterations in lipid metabolism, include actions on all components of the vascular wall (endothelial, smooth muscle, and adventitial cells), neurons, and blood elements (platelets and leukocytes). Changes in production of nitric oxide (NO) have been implicated as one of the cellular biochemical-related pathways regulated by estrogen that may contribute to gender and hormonal differences in the progression of cardiovascular disease. [3][4][5][6][7][8][9] NO is synthesized from L-arginine by the enzyme nitric oxide synthase (NOS). NOS consists of three isoforms: type I, neuronal; type II, inducible; and type III, endothelial/ constitutive. In this issue of Circulation Research, García-Durán et al 10 add to the accumulating body of evidence suggesting that estrogen directly modulates expression of NOS, in particular the neuronal isoform (type I) in neutrophils. With use of Western blot analysis of protein isolated from neutrophils, levels of neuronal NOS were greater in neutrophils from premenopausal women during the ovulatory phase of the estrus cycle when estrogen is high compared with the follicular phase when circulating levels of estrogen fall. In addition, expression of neuronal NOS increased in neutrophils of postmenopausal women who were using transdermal estrogen replacement (50 mg/d) for 4 months. The range of circulating estrogen over which these changes in neuronal NOS occurred was physiological, between 5ϫ10 Ϫ10and 2ϫ10Ϫ9 mol/L. These observations suggest that changes in circulating levels of oxidized products of nitric oxide in blood of women during different stages of the estrus cycle as well as with estrogen replacement therapy may be derived from cells other than the those of the endothelium. [11][12][13][14] García-Durán et al 10 examined the gender specificity of estrogen on expressional control of neuronal NOS using neutrophils from male subjects. In these cells, there was both a time and dose dependency of induction of neuronal NOS by estrogen. This induction was receptor mediated and showed biphasic stimulation with increases in NOS from 10 Ϫ10 to 10 Ϫ8 mol/L of estrogen and inhibition at higher concentrations. These concentration ranges are similar to those shown to stimulate neuronal NOS isolated from rabbit cerebellum. 15 The observation that estrogen can modulate NOS isoform in male cells is consistent with observations of increases in reactive hyperemia, a vascular response mediated by endothelium-derived NOS, in male to female transsexuals. 16 As provocative as these results might be, much remains to be learned regarding effects of sex steroid hormones on leukocyte function and how these effects relate to g...

Experimental Abdominal Aortic Aneurysms in Mice Lacking Expression of Inducible Nitric Oxide Synthase

“…Although it remains unclear why these effects might occur in a sexselective fashion and how they are related to circulating ovarian hormones, there is increasing evidence that interactions between estrogen and cellular NOS expression can influence NO production in various pathophysiologic states. 53,[65][66][67][68] More comprehensive studies will be needed to elucidate the apparent interaction between ovarian hormones and NO production during aneurysm formation in female mice.…”

Aerobic exercise training promotes additional cardiac benefits better than resistance exercise training in postmenopausal rats with diabetes

“…4<6 Although the mechanisms through which the prevalence of cardiac diseases increases during the climacteric stage are not well established, estrogen has been suggested to play a cardioprotective role in women before menopause, thus reducing the incidence of these diseases in relation to men. 7 Indeed, individuals with diabetes are more prone to congestive cardiac insufficiency, regardless of the presence of coronary disease or hypertension, and CVD is the leading cause of mortality among individuals with diabetes. Diabetic cardiomyopathy is now well documented in experimental, clinical, and epidemiological studies.…”

Estrogen Receptor α and Endothelial Nitric Oxide Synthase Are Organized Into a Functional Signaling Module in Caveolae

“…4 -6 Estrogen has important atheroprotective properties that are at least partially related to its capacity to enhance the bioavailability of nitric oxide (NO). [5][6][7] NO is a potent regulator of blood pressure, platelet aggregation, leukocyte adhesion, and vascular smooth muscle mitogenesis that is produced in the vascular wall primarily by the endothelial isoform of NO synthase (eNOS) on the conversion of the substrate L-arginine to L-citrulline. 8 The function of the L-arginine/eNOS system is altered in a variety of vascular disorders.…”