Abstract
BackgroundAlthough the mechanisms underlying the beneficial effects of estrogen on cerebrovascular function are well known, the age-dependent deleterious effects of estrogen are largely unstudied. It was hypothesized that age and sex interact in modulating cerebrovascular reactivity to vasopressin (VP) by altering the role of prostanoids in vascular function.MethodsFemale (F) Sprague–Dawley rats approximating key stages of “hormonal aging” in humans were studied: premenopausal (mature multigravid, MA, cyclic, 5–6 months) and postmenopausal (reproductively senescent, RS, acyclic, 10–12 months). Age-matched male (M) rats were also studied. Reactivity to VP (10−12–10−7 M) was measured in pressurized middle cerebral artery segments in the absence or presence of selective inhibitors of COX-1 (SC560, SC, 1 μM) or COX-2 (NS398, NS, 10 μM). VP-stimulated release of PGI2 and TXA2 were measured using radioimmunoassay of 6-keto-PGF1α and TXB2 (stable metabolites, pg/mg dry wt/45 min).ResultsIn M, there were no changes in VP-induced vasoconstriction with age. Further, there were no significant differences in basal or in low- or high-VP-stimulated PGI2 or TXA2 production in younger or older M. In contrast, there were marked differences in cerebrovascular reactivity and prostanoid release with advancing age in F. Older RS F exhibited reduced maximal constrictor responses to VP, which can be attributed to enhanced COX-1 derived dilator prostanoids. VP-induced vasoconstriction in younger MA F utilized both COX-1 and COX-2 derived constrictor prostanoids. Further, VP-stimulated PGI2 and TXA2 production was enhanced by endogenous estrogen and decreased with advancing age in F, but not in M rats.ConclusionsThis is the first study to examine the effects of age and sex on the mechanisms underlying cerebrovascular reactivity to VP. Interestingly, VP-mediated constriction was reduced by age in F, but was unchanged in M rats. Additionally, it was observed that selective blockade of COX-1 or COX-2 produced age-dependent changes in cerebrovascular reactivity to VP and that VP-stimulated PGI2 and TXA2 production were enhanced by endogenous estrogen in younger F. A better understanding of the mechanisms by which estrogen exerts its effects may lead to new age- and sex-specific therapeutic agents for the prevention and/or treatment of cerebrovascular diseases.
Highlights
The mechanisms underlying the beneficial effects of estrogen on cerebrovascular function are well known, the age-dependent deleterious effects of estrogen are largely unstudied
Body weight did not differ with age in F (MA F 303 ± 5.8 g; reproductively senescent (RS) F 303 ± 9.5 g; P > 0.05); RS M were significantly heavier than multigravid adult (MA) M (MA M 491 ± 10.9 g; RS M 559 ± 12.3 g; P ≤ 0.01)
Body weights were significantly different between M and F in both young MA and older RS rats (P ≤ 0.01)
Summary
The mechanisms underlying the beneficial effects of estrogen on cerebrovascular function are well known, the age-dependent deleterious effects of estrogen are largely unstudied. Disruption of the endocrine environment, both during menopause and with advancing age, contributes to dramatic increases in the incidence of neurodegenerative and vascular diseases, especially stroke. While both endogenous estrogens and estrogen replacement therapy following surgical menopause exert beneficial effects in younger females (F), age and/or estrogen replacement therapy appear to be detrimental in older, postmenopausal F. It is important to determine how age and sex interact in the regulation of cerebrovascular prostanoid production and the enhancement of both vasoconstriction and hemostasis, and how these mechanisms may differ between males (M) and F with age
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