Estrogen promotes microvascular pathology in female stroke-prone spontaneously hypertensive rats (SHRSP)

Abstract

Estrogen produces both beneficial and adverse effects on cardiovascular health via mechanisms that remain unclear. Female SHRSP maintainedon a high-salt intake rapidly develop stroke and malignant nephrosclerosis. To determine whether estrogen contributes to stroke-related mortality in this model, we examined the effect of ovariectomy with or without estradiol benzoate (E2) therapy and antiestrogen treatment with tamoxifen. SHRSP were ovariectomized (Ovex) or sham operated (Sham) at 4 weeks of age and then dosed chronically with E2 at 10 μg/Kg 3 times a week or vehicle (VEH) starting at 5 weeks of age. All SHRSP received 1% NaCl drinking solution starting at 8 weeks of age. Ovex rats lived significantly (P<0.01) longer (15.1±0.3 weeks, n=4) than Sham (13.6±0.2 weeks, n=6) or Ovex & E2 (12.4±0.2 weeks, n=7). In a second survival study, six saline-drinking female SHRSP with intact ovaries received 2.3 mg/Kg of tamoxifen 3 times a week and six non-ovariectomized littermates received VEH. Tamoxifen treatment delayed the onset of stroke-related mortality by at least two weeks (P<0.01) but did not prevent the development of severe hypertension. Ovex (n=13), Sham (n=14), and Ovex & E2 (n=9) SHRSP that were sacrificed at 11.5 weeks of age were also studied so that renal microvascular injury could be assessed in groups that were matched for age. Systolic blood pressure (SBP) prior to death was lower in Ovex compared with Sham and Ovex & E2 but did not differ between Sham and Ovex & E2 (Table). Ovex & E2had elevated blood urea nitrogen (BUN), proteinuria and renal lesions of thrombotic microangiopathy (TMA) compared with either Sham or Ovex. Ovex & E2 developed worse pathology than Sham, perhaps due to the absence of vascular protective factors from the ovary. Consistent with the ability of Ovex to diminish endogenous estrogen levels, uterine dry weight (mg) was significantly less in Ovex (8±1) compared to Sham (76±4) and Ovex & E2 (59±3). The results of these studies suggest that estrogen plays a role in promoting stroke and renal microvascular injury in saline-drinking female SHRSP. Values are mean ± SEM; P<0.01 vs Ovex; #P<0.01 vs Sham Values are mean ± SEM; P<0.01 vs Ovex; #P<0.01 vs Sham