Calcium Dependent NOS Induction by Sex Hormones: Estrogen
Reporter and Curator: Sudipta Saha, Ph.D.
Nitric oxide (NO) synthases (NOSs) constitute a family of isozymes that catalyze the oxidation of L-arginine to NO and citrulline. First identified in the vascular endothelium, NO synthesis has subsequently been shown to play important roles in:
- the regulation of vascular and gastrointestinal tone,
- in cell-mediated cytotoxicity against bacteria and tumors, and
- in a variety of central and peripheral nervous system activities.
NOSs can be divided into three functional classes based on their sensitivity to calcium.
- The cytokine- or bacterial product-inducible isoenzyme iNOS binds calmodulin tightly at resting intracellular calcium concentrations.
- The constitutive forms, isozymes eNOS (originally described in endothelial cells) and
- nNOS (originally described in neuronal tissue), bind calmodulin in a reversible and calcium-dependent fashion.
The mechanisms by which their synthesis is controlled are unknown. The cDNA species encoding the rat, mouse, and human nNOS, the human and bovine eNOS, and iNOS from several species and cell types have been cloned and sequenced. The three human isozymes characterized to date are distinct, with their deduced protein sequences showing only 50-60%o amino acid identity. nNOS, which in rats and humans localizes to neurons in the central and peripheral nervous system and colocalizes with NADPHdiaphorase activity, has also been shown to be widely distributed in several non-neuronal tissues including human skeletal muscle.
It had been thought that both nNOS and eNOS were purely constitutive enzymes, although studies suggest eNOS may be induced by shear stress. Studies demonstrate that these NOSs can be induced in several tissues during pregnancy and in nonpregnant female and male animals by estradiol and that in skeletal muscle it is accompanied by an increase in NOS-specific mRNA.
Evidences emerging from various laboratories showed that there is an increase in the release of NO from the vasculature during pregnancy. Furthermore, treatment of pregnant animals at the end of gestation with tamoxifen reduced NOS activity in the cerebellum, an organ where tamoxifen acts as a pure estrogen-receptor antagonist. Thus, the increase in calcium-dependent NOS activity during pregnancy is mediated by estrogen. This conclusion is supported by the fact that treatment of nonpregnant females and male animals with estradiol also increased calcium-dependent NOS activity in all tissues studied.
Interestingly, testosterone treatment also increased cerebellar NOS activity without affecting other tissues. However, testosterone may increase brain NOS by directly binding estrogen receptors as has been reported. Furthermore, the cerebellum was the only tissue in the male to respond to a 5-day course of estradiol, suggesting that it may have a larger number and/or a greater availability of estrogen receptors than other tissues. In addition, the brain is rich in aromatase, which converts testosterone into estradiol. This, together with the observation that progesterone does not induce NOS, indicates that the induction of both nNOS and eNOS is specific for estrogen and not a characteristic of all sex steroids. These experiments do not exclude the possibility that the addition of progesterone might modify the estradiol effect.
The increases in NOS activity are the result of augmented enzyme synthesis (enzyme induction) since they are accompanied by increases in the specific mRNAs for both eNOS and nNOS. It is not, however, possible to tell whether the increases in mRNA are caused by an upregulation of mRNA synthesis (transcriptional induction) or decreased mRNA breakdown.
Although calcium-dependent NOS activity was increased by estradiol in tissues obtained from both female and male guinea pigs, a longer duration of treatment was necessary in the male. The most likely explanation for this observation is that the number or availability of estrogen receptors is initially too low in most tissues of the male and requires a period of estrogen priming. Although other factors may play a role, the duration of exposure may well explain the observation that the effect of pregnancy on NOS-specific mRNA is greater than estradiol alone.
The observation that estradiol induces calcium-dependent NOSs has several important implications:
- An increase in release of NO from the endothelium would decrease vascular tone and contractility, events that are characteristic in pregnancy.
- Heterogeneity among tissue endothelium regarding the effects of estrogen on basal NO release could explain the selective redistribution of maternal cardiac output to organs important for a successful pregnancy.
- Consistent with this possibility is the observation that the effect of pregnancy on endothelium-derived NO is greatest in the uterine artery, followed by the mesenteric artery and then renal arteries.
- An alternative hypothesis to explain the adaptation of smooth muscle to pregnancy is that it is caused by prostacyclin. Prostacyclin is increased during pregnancy and contributes to the observed reduced contractility of the ovine uterine artery to angiotensin II.
However, estradiol does not increase the synthesis of prostacyclin by the endothelium, nor does inhibition of prostacyclin synthesis prevent the effects of pregnancy on smooth muscle. In addition, both the incidence of esophageal reflux and the gastrointestinal transit time are increased during pregnancy. Although this phenomenon has previously been attributed to a direct effect of progesterone, NO is a powerful dilator of the gastrointestinal smooth muscle. If the increase in NOS activity observed in the esophagus applies to the bowel, enhanced NO might be the mechanism underlying both increased esophageal reflux and transit time.
The biological signifcance of an estradiol-dependent increase in the NOS in the central nervous system is of great interest and deserves further investigation. Furthermore, an estradiol-mediated increase in NOS in the vasculature could be the mechanism whereby premenopausal women are protected from coronary artery disease since increased NOS may slow the development of atherosclerosis and reduce the contractile response to acute thrombosis. Finally, the induction of calcium-dependent NOS enzymes by estradiol suggests that the present classification of this family of enzymes into constitutive and inducible types needs to be revised, since eNOS and nNOS enzymes at least are both constitutive and inducible.
Source References:
http://www.ncbi.nlm.nih.gov/pubmed?term=Calcium%20dependent%20NOS%20induction%20by%20sex%20hormones
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Calcium dependent NOS induction by sex hormones: Estrogen
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http://pharmaceuticalintelligence.com/2012/10/03/calcium-dependent-nos-induction-by-sex-hormones/
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http://pharmaceuticalintelligence.com/2012/08/16/no-and-platelet-aggregation/
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