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

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.

Age-Related Reductions in Cerebrovascular Reactivity Using 4D Flow MRI

“…Because men and women exhibit distinctive features of cerebrovascular disease etiology and clinical outcomes (Carter et al, 2012; Haast et al, 2012), and sex hormones influence the cerebrovasculature (Deer and Stallone, 2016), we sought to determine if age-related differences in CVR were sex-specific. Our findings were twofold.…”

“…In addition, the older participants in previous studies often include those with higher vascular risk (i.e., lack of physical exercise or hypertension), which may confound the effect of age. Furthermore, many studies do not address sex-related differences due to unequal distributions of men and women, and because sex hormones influence the cerebrovasculature, the effect of aging on CVR may be sex-specific (Miller et al, 2013; Deer and Stallone, 2016). Lastly, the controversy in the literature may be due to the fact that the majority of existing work, including our previous work, relies on non-invasive imaging techniques including transcranial Doppler ultrasound (TCD) (Aaslid et al, 1982), which tracks blood velocity of the large intracranial vessels but operates on the assumption that the blood vessel diameter does not change in response to an environmental perturbation such as hypercapnia (Serrador et al, 2000).…”

Benefits of exercise training on cerebrovascular and cognitive function in ageing

“…65 In animal models, ROS production has been demonstrated to be a key factor leading to endothelial dysfunction, cerebrovascular dysfunction and cognitive impairment. [66][67][68] Further, there is increased uncoupling of endothelial nitric oxide synthase (eNOS) in ageing, resulting from a diminished L-arginine supply, 69,70 and increased concentrations of asymmetrical dimethylarginine, which acts as a competitive inhibitor of eNOS, thus reducing NO biosynthesis. 71 Endothelial dysfunction may also be induced by hormonal imbalances and increased angiotensin Table 1.…”

Oxytocin Reduces Intravesical Pressure in Anesthetized Female Rats: Action on Oxytocin Receptors of the Urinary Bladder

“…Because of that, topical administration of oxytocin onto the urinary bladder of ovariectomized rats was not performed. Plasma estrogen was not measured in the present study, which is a limitation of the present study, nevertheless, it would be expected that the rats were at least in a hypoestrogenism condition after 21 days as it has been shown in earlier studies (Deer and Stallone, 2016). and at 30 min after blockade of oxytocin receptors (OTr) (10 ug/kg, i.v.)…”

“…At the end of surgery, the rats received a single dose of Veterinary Pentabiotic for Small Animals (2,000 U/mL, i.m., FortDodge, Campinas, Brazil) as a prophylactic procedure and tramadol (10 mg/kg, i.m., Tramal R , Pfizer, Sao Paulo, Brazil) at the end of surgery and every 12 h in the immediate post-operative period (1 day after surgery). The animals recovered from surgery for 21 days in order to reduce the circulating estrogen levels, in accordance to earlier studies (Deer and Stallone, 2016). Sham rats underwent the same surgical procedures, but the ovaries were not removed.…”