Ethinylestradiol does not enhance the expression of nitric oxide synthase in bovine endothelial cells but increases the release of bioactive nitric oxide by inhibiting superoxide anion production.

Abstract

Estradiol is known to exert a protective effect against the development of atherosclerosis, but the mechanism by which this protection is mediated is unclear. Since animal studies strongly suggest that production of endothelium-derived relaxing factor is enhanced by estradiol, we The incidence of cardiovascular disease, the leading cause of mortality in western societies, is higher in men than in premenopausal women but increases in postmenopausal women. An abundance of epidemiological data supports a role for estrogens in this atheroprotective effect, prompting recommendations for their widespread use in postmenopausal replacement therapy (1, 2). However, the mechanism whereby this protection is mediated remains obscure. It is traditionally thought to be due to potentially favorable changes in blood lipids and lipoproteins (1), but a number of human (3) as well as animal studies strongly suggest a direct effect on the vascular system (4-6) and more specifically that basal endotheliumderived relaxing factor is enhanced in estradiol-treated females compared with oophorectomized controls (7-11).The endothelium-derived relaxing factor has been identified as nitric oxide (NO) or a closely related compound derived from the amino acid L-arginine, able to induce stimulation of the soluble guanylate cyclase enzyme contained in vascular smooth muscle cells (12)(13)(14) Because the molecular mechanisms of the endotheliumderived relaxing factor-enhanced activity observed in estradiol-treated animals has not yet been precisely elucidated, we sought to determine the effects of estradiol on NO production and simultaneously on NOS mRNA, protein, and activity in a well-characterized culture system of endothelial cells. MATERIALS AND METHODSCell Culture and Materials. Bovine aortic endothelial cells (BAEC) were obtained and grown as described (25,26)

Expression of estrogen receptors in the coronary arteries of young and premenopausal women in relation to central obesity

“…22 The localization of ER in the coronary plaques was very similar to that observed earlier with oxidized low-density lipoprotein. 23 It is also possible that women with abdominal obesity may have functional disturbances in their ERs, or that their arterial tissues express variant forms of ER which may have anomalous transcriptional activities and may inhibit or enhance the effect of wild-type receptors.…”

Estrogens Increase Transcription of the Human Endothelial NO Synthase Gene

“…A recent study on bovine endothelial cells claimed that 17␣-ethinyl estradiol did not enhance the expression of NOS III but that it increased the release of bioactive NO by inhibiting superoxide anion production. 23 In the current study we demonstrate that 17␣-ethinyl estradiol and 17␤-estradiol enhance NOS III mRNA and protein expression, whereas other steroid hormones do not. The increased NOS III expression results from an increased NOS III promoter activity with unchanged mRNA stability.…”

“…23 The enzyme or enzymes responsible for superoxide production and potentially regulated by estrogens have not been identified. Our cell model does show an increase in NOS III mRNA and protein in response to estrogens and therefore mimics the in vivo situation described by other groups.…”

Apoptosis in the vasculature: mechanisms and functional importance

“…Oestradiol treatment of HUVEC in culture results in a dose-dependent, receptor-mediated inhibition of TNF-a-induced apoptosis and activation of the caspase-1 pathway (Spyridipoulos et al, 1997). Moreover, oestrogen administration increases the release of bioactive nitric oxide by inhibiting superoxide anion production (Arnal et al, 1996). These data suggest that the bene®cial atheroprotective e ects of oestradiol may result, at least in part, from the preservation of endothelial integrity and prevention of vessel thrombosis.…”

“…FGF-2 +/7 bcl-2* (Karsan et al, 1997) . Estradiol NO (Arnal et al, 1996), caspase inhibition (Alvarez et al, 1997;Spyridopoulos et al, 1997) . Haeme oxygenase-1 bcl-2*?…”