Effects of estrogen on cerebrovascular function: age-dependent shifts from beneficial to detrimental in small cerebral arteries of the rat - PubMed (original) (raw)

Effects of estrogen on cerebrovascular function: age-dependent shifts from beneficial to detrimental in small cerebral arteries of the rat

Rachel R Deer et al. Am J Physiol Heart Circ Physiol. 2016.

Abstract

In the present study, interactions of age and estrogen in the modulation of cerebrovascular function were examined in small arteries <150 μM. The hypothesis tested was that age enhances deleterious effects of exogenous estrogen by augmenting constrictor prostanoid (CP)-potentiated reactivity of the female (F) cerebrovasculature. F Sprague-Dawley rats approximating key stages of "hormonal aging" in humans were studied: perimenopausal (mature multi-gravid, MA, cyclic, 5-6 mo of age) and postmenopausal (reproductively senescent, RS, acyclic 10-12 mo of age). Rats underwent bilateral ovariectomy and were given estrogen replacement therapy (E) or placebo (O) for 14-21 days. Vasopressin reactivity (VP, 10(-12)-10(-7) M) was measured in pressurized middle cerebral artery segments, alone or in the presence of COX-1- (SC560, 1 μM) or COX-2- (NS398, 10 μM) selective inhibitors. VP-stimulated release of prostacyclin (PGI2) and thromboxane (TXA2) were assessed by radioimmunoassay of 6-keto-PGF1α and TXB2 (stable metabolites). VP-induced vasoconstriction was attenuated in ovariectomized + estrogen-replaced, multigravid adult rats (5-6 mo; MAE) but potentiated in older ovariectomized + estrogen-replaced, reproductively senescent rats (12-14 mo; RSE). SC560 and NS398 reduced reactivity similarly in ovariectomized multigravid adult rats (5-6 mo; MAO) and ovariectomized reproductively senescent rat (12-14 mo; RSO). In MAE, reactivity to VP was reduced to a greater extent by SC560 than by NS398; however, in RSE, this effect was reversed. VP-stimulated PGI2 was increased by estrogen, yet reduced by age. VP-stimulated TXA2 was increased by estrogen and age in RSE but did not differ in MAO and RSO. Taken together, these data reveal that the vascular effects of estrogen are distinctly age-dependent in F rats. In younger MA, beneficial and protective effects of estrogen are evident (decreased vasoconstriction, increased dilator prostanoid function). Conversely, in older RS, detrimental effects of estrogen begin to be manifested (enhanced vasoconstriction and CP function). These findings may lead to age-specific estrogen replacement therapies that maximize beneficial and minimize detrimental effects of this hormone on small cerebral arteries that regulate blood flow.

Keywords: cyclooxygenase; middle cerebral artery; prostacyclin; thromboxane; vasoconstriction.

Copyright © 2016 the American Physiological Society.

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Figures

Fig. 1.

Fig. 1.

Concentration-response curves for vasopressin (VP) in endothelium-intact pressurized middle cerebral artery segments prepared from MAO, MAE, RSO, and RSE Sprague-Dawley female rats. Mature multigravid adult female rats (MA, 4–6 mo), either ovariectomized (MAO) or ovariectomized and estrogen-replaced (MAE), and reproductively senescent female rats (RS; 10–12 mo), either ovariectomized (RSO) or ovariectomized and estrogen-replaced (RSE). Data points represent means ± SE (n = 6 or 7 rats/group). MAO, MAE, RSO, and RSE were compared statistically; a–f0.0001 ≤ P ≤ 0.009, mean values without common superscript differ significantly at middle and maximal concentrations of VP. At middle VP, MAE, and RSO differ significantly from MAO and RSE, and MAO differs significantly from RSE. At maximal VP, MAE differs significantly from MAO, RSO, and RSE. MAO and RSO do not differ.

Fig. 2.

Fig. 2.

Concentration-response curves for VP in endothelium-intact pressurized middle cerebral artery segments prepared from MAO, MAE, RSO, and RSE female Sprague-Dawley rats in the presence of selective COX inhibitors SC560 (COX-1; 1 μM), NS398 (COX-2; 10 μM), or vehicle-control (CTL). Vessels were prepared in triplicate from each experimental group: mature multigravid adult female rats (MA, 4–6 mo.), either ovariectomized (MAO) (A) or ovariectomized and estrogen-replaced (MAE) (B), and reproductively senescent female rats (RS, 10–12 mo), either ovariectomized (RSO) (C) or ovariectomized and estrogen-replaced (RSE) (D). Data points represent means ± SE (n = 6 or 7 rats/group). CTL, SC560 (COX-1), and NS398 (COX-2) treatments were compared statistically for each experimental group (i.e., MAO, MAE, RSO, or RSE). a–f_P_ ≤ 0.0001, mean values without common superscript differ significantly at middle and maximal concentrations of VP. For MAO, CTL differs significantly from SC560 (COX-1) and NS398 (COX-2) at both middle and maximal VP. SC560 (COX-1) and NS398 (COX-2) differ significantly at middle VP only. For MAE, CTL, SC560 (COX-1), and NS398 (COX-2), all differ significantly from one another at both middle and maximal VP. For RSO, NS398 (COX-2) differs significantly from CTL and SC560 (COX-1) at middle VP; CTL differs significantly from SC560 (COX-1) and NS398 (COX-2) at maximal VP. For RSE, CTL, SC560 (COX-1), and NS398 (COX-2) all differ significantly from one another at both middle and maximal VP.

Fig. 3.

Fig. 3.

Basal and VP-stimulated (low concentration, 10−9 M; or high concentration 10−7 M) release of 6-keto-PGF1α by middle cerebral artery segments from MAO, MAE, RSO, and RSE female Sprague-Dawley rats. Mature multigravid adult female rats (MA; 4–6 mo.), either ovariectomized (MAO) or ovariectomized and estrogen-replaced (MAE), and reproductively senescent female rats (RS; 10–12 mo.), either ovariectomized (RSO) or ovariectomized and estrogen-replaced (RSE). Values are means ± SE; n = 6 rats/group. Basal, low-VP, and high-VP prostanoid release were compared statistically within each experimental group (i.e., MAO, MAE, RSO, or RSE). a–c_P_ ≤ 0.0001, mean values within groups (MAO, MAE, RSO, RSE) without common superscript are significantly different. Basal, low-VP, and high-VP all differ significantly from one another in each experimental group. Basal, low-VP, or high-VP treatments were compared statistically among the four experimental groups (i.e., MAO vs. MAE vs. RSO vs. RSE). *,#,+0.0001 ≤ P ≤ 0.02 mean values between groups (MAO vs. MAE vs. RSO vs. RSE) with different superscripts are significantly different. Basal prostanoid release did not differ among the four experimental groups. In low-VP prostanoid release, MAO and RSO differ significantly from MAE and RSE. In high-VP prostanoid release, MAO and RSO differ significantly from MAE and RSE, and MAE and RSE differ from each other.

Fig. 4.

Fig. 4.

Basal and VP-stimulated (low concentration, 10−9 M; or high concentration 10−7 M) release of TXB2 by middle cerebral artery segments from MAO, MAE, RSO, and RSE female Sprague-Dawley rats. Mature multigravid adult female rats (MA; 4–6 mo.), either ovariectomized (MAO) or ovariectomized and estrogen-replaced (MAE), and reproductively senescent female rats (RS; 10–12 mo.), either ovariectomized (RSO) or ovariectomized and estrogen-replaced (RSE). Values are means ± SE; n = 6 rats/group. Basal, low-VP, and high-VP prostanoid release were compared statistically within each experimental group (i.e., MAO, MAE, RSO, or RSE). a–c0.0001 ≤ P ≤ 0.003, mean values within groups (MAO, MAE, RSO, RSE) without common superscript are significantly different. Basal, low-VP, and high-VP all differ significantly from one another in MAE and RSE; basal and low-VP differ significantly from high-VP in MAO and RSO. Basal, low-VP, or high-VP treatments were compared statistically among the four experimental groups (i.e., MAO vs. MAE vs. RSO vs. RSE). *,#,+0.0001 ≤ P ≤ 0.003 mean values between groups (MAO vs. MAE vs. RSO vs. RSE) with different superscripts are significantly different. Basal prostanoid release did not differ among the four experimental groups. In low-VP prostanoid release, MAO and RSO differ significantly from MAE and RSE. In high-VP prostanoid release, MAO and RSO differ significantly from MAE and RSE, and MAE and RSE differ from each other.

Fig. 5.

Fig. 5.

Schematic diagram of a proposed model of the interactions between age and estrogen in the regulation of cerebrovascular function, based upon the present studies. The distinctly age-dependent effects of estrogen in the cerebrovasculature of the female rat are depicted in this model. In younger MA, beneficial and protective effects of estrogen are evident (decreased vasoconstriction, increased dilator prostanoid function). In older RS, detrimental effects of estrogen begin to be manifested (enhanced vasoconstriction and constrictor prostanoid function). AA, arachidonic acid; COX-1, cyclooxygenase-1; COX-2, cyclooxygenase-2; MA, mature multigravid adult; MCA, middle cerebral artery; PGI2, prostacyclin; RS, reproductively senescent; TXA2, thromboxane; V1, vasopressin-1 receptor; V2, vasopressin-2 receptor; VP, vasopressin.

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