Aging Negatively Affects Estrogens-Mediated Effects on Nitric Oxide Bioavailability by Shifting ERα/ERβ Balance in Female Mice

Abstract

AimsAging is among the major causes for the lack of cardiovascular protection by estrogen (E2) during postmenopause. Our study aims to determine the mechanisms whereby aging changes E2 effects on nitric oxide (NO) production in a mouse model of accelerated senescence (SAM).Methods and ResultsAlthough we found no differences on NO production in females SAM prone (SAMP, aged) compared to SAM resistant (SAMR, young), by either DAF-2 fluorescence or plasmatic nitrite/nitrate (NO2/NO3), in both cases, E2 treatment increased NO production in SAMR but had no effect in SAMP. Those results are in agreement with changes of eNOS protein and gene expression. E2 up-regulated eNOS expression in SAMR but not in SAMP. E2 is also known to increase NO by decreasing its catabolism by superoxide anion (O2 -). Interestingly, E2 treatment decreased O2 − production in young females, while increased O2 − in aged ones. Furthermore, we observed that aging changed expression ratio of estrogen receptors (ERβ/ERα) and levels of DNA methylation. Increased ratio ERβ/ERα in aged females is associated to a lack of estrogen modulation of NO production and with a reversal in its antioxidant effect to a pro-oxidant profile.ConclusionsTogether, our data suggest that aging has detrimental effects on E2-mediated benefits on NO bioavailability, partially by affecting the ability of E2 to induce up regulation of eNOS and decrease of O2 −. These modifications may be associated to aging-mediated modifications on global DNA methylation status, but not to a specific methylation at 5′flanking region of ERα gene.

Treatment with QiBaoMeiRan, a Kidney-Invigorating Chinese Herbal Formula, Antagonizes Estrogen Decline in Ovariectomized Rats

“…It is worth mentioning that the stimulation of estrogen synthesis in our OVX animals agreed with the previous studies when the OVX rats were treated with other phytoestrogens. 13,29 Under physiological conditions, the biological effects of estrogen depend not only on the level of estrogen but also on the distribution and expression levels of the corresponding ERs, ERa and ERb, in the target cell [30][31][32] Estrogen and ERs are involved in the physiological function regulation of the female reproductive system. In this study, QBMR significantly up-regulated the expression of ERa and ERb in protein and gene levels in the target tissues, respectively.…”

“…The sections were then stained with 3,3¢-diaminobenzidine (DAB) (Sigma). 13 The Image-Pro Plus 6.0 System image analysis system was used for quantitative analysis.…”

Estrogen synthesis and signaling pathways during aging: from periphery to brain

“…However, unlike ERβ plays an important neuroprotective role in the central nervous system, in the heart, ERα appears to play a prominent role in most of the other tissues. The critical role of ERa in heart is evidenced by findings from another study showed a increased the ratio of ERβ/ERα in both vascular endothelium and smooth muscle in aged female mice causes the reversal in the antioxidant effect of estrogen to a pro-oxidant profile and is responsible for the increased oxidative stress during aging [112]. In addition, estrogen can reduce ischemia and reperfusion injury and preserve cardiac function via GPR30 and transactivating epidermal growth factor receptors [113].…”

Estrogen Effects on Vascular Inflammation Are Age Dependent

“…For example, variation in methylation-associated inactivation of ER gene promoters in various tissue-types, including in the cardiovascular system, has been described in aging rodents and humans. 42,43 The hypermethylation of ERα with aging is more impressive when taken in context of the global hypomethylation of the genome that accompanies the aging process. 44 It is important to mention that the observed changes in ERα expression with aging are cell-type specific since they are not seen in VSMCs and that age-dependent change in ERα expression does not account for the paradoxical effect of E2 on CRP-induced inflammatory mediator expression in VSMCs.…”