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

Abstract

Estrogen produces both beneficial and adverse effects on cardiovascular health via mechanisms that remain unclear. Stroke-prone spontaneously hypertensive rats (SHRSP) maintained on Stroke-Prone Rodent Diet and 1% NaCl drinking water (starting at 8 wk of age) rapidly develop stroke and malignant nephrosclerosis that can be prevented, despite continued hypertension, by drugs targeting angiotensin II and aldosterone actions. This study evaluated estrogen's effects in the SHRSP model. Female SHRSP that were sham operated (SHAM), ovariectomized (OVX) at 4 wk of age, or OVX and treated with estradiol benzoate (E2,30 microg x kg-1 x wk-1) were studied. In a survival protocol, OVX rats lived significantly longer (15.1 +/- 0.3 wk) compared with SHAM (13.6 +/- 0.2 wk) or OVX+E2 rats (12.4 +/- 0.2 wk). In a protocol in which animals were matched for age, at 11.5 wk, terminal systolic blood pressure and urine protein excretion were elevated in SHAM and OVX+E2 rats compared with OVX rats; blood urea nitrogen, renal microvascular and glomerular lesions, and plasma renin concentration were elevated in OVX+E2 relative to SHAM or OVX rats. In a survival protocol using intact female SHRSP, treatment with an antiestrogen (tamoxifen, 7 mg.kg-1.wk-1) prolonged survival by >2 wk compared with controls (P < 0.01). The data indicate that estrogen promotes microangiopathy in the kidney and stroke in saline-drinking SHRSP.

Effects of Estrogen on Cardiovascular Injury in Ovariectomized Female DahlS.Z- Lepr fa /Lepr fa Rats as a New Animal Model of Metabolic Syndrome

“…42 In stroke-prone SHRs, ovariectomy reduced stroke and renal injury, whereas estrogen replacement increased such injury. 14 In hypertensive mRen2.Lewis female rats on a high-salt diet, ovariectomy reduced proteinuria, renal injury, and the blood level of the inflammatory marker C-reactive protein. 43 Our observation that E 2 treatment promoted cardiac inflammation in Ovx-DS/obese rats is consistent with the results of these previous studies.…”

“…11 However, other studies suggest that estrogen activates the renin-angiotensin-aldosterone system (RAAS), an action that might contribute to cardiac injury. [12][13][14][15] In humans, estrogen increases circulating levels of angiotensin II (Ang II), 12 as well as intrarenal Ang II activity, 13 with the latter effect being associated with a decrease in renal blood flow. In animal models of cardiovascular injury attributed to an activated RAAS, estrogen increases the incidence of stroke and renal injury.…”

“…In animal models of cardiovascular injury attributed to an activated RAAS, estrogen increases the incidence of stroke and renal injury. 14,15 We recently established a new animal model of MetS, the DahlS.Z-Lepr fa /Lepr fa (DS/obese) rat, by crossing Dahl saltsensitive (DS) rats with Zucker rats harboring a missense mutation in the leptin receptor gene (Lepr). When fed a normal diet, male DS/obese rats develop a phenotype similar to MetS in humans, including hypertension.…”

Sexual Dimorphism of the Aging Kidney: Role of Nitric Oxide Deficiency

“…There are ER-independent actions of estrogen on kidney that increase the prosclerotic IGF in the db/db D2 mouse kidney and overwhelm any protective actions of ER stimulation (44). Estradiol promotes renal injury and stroke in the stroke-prone SHR (98) and increases renal damage with both chronic NOS inhibition and ANGII infusion in female rats (75). Also, the progression of CKD is faster in the female analbuminemic rat and the Zucker obese rat (32, 42) in association with more severe hypertriglyceridemia.…”

Functional and structural remodeling of the myocardial microvasculature in early experimental hypertension

“…Notably, we also used female pigs, and estrogen has been reported to increase angiogenic response in HT (40). However, the pigs in our experimental groups were pre-menstrual, so that hormonal changes were unlikely to interfere with our results.…”