Estradiol is not protective against angiotensin II-induced hypertension in middle-aged ovariectomized rats

Menopause leads to loss of cardiovascular and renal protection, and while hormone therapy offers benefits, its efficacy may depend on health status at menopause onset. We hypothesized that preexisting hypertension blunts the renal, cardiac, and vascular effects of Estradiol (E2). Female Long-Evans rats were ovariectomized (OVX) at 46 weeks to model menopause and received either E2 or vehicle, and some were infused with angiotensin II (ANG; 700 ng/kg/min) 4 weeks before OVX. Blood pressure (BP) was measured by tail cuff, renal function by urine collection, collagen deposition by histology, and mRNA expression in aorta and kidney by droplet digital PCR. ANG increased BP and proteinuria (p = 0.02), water intake (p < 0.001), urinary output, heart weight, and aortic NOX4 (p < 0.01), confirming hypertension and oxidative stress. E2 reduced body weight (p = 0.02), increased bone mineral content (p = 0.01), and prevented uterine atrophy (p < 0.001), confirming E2 treatment. While E2 attenuated cardiac hypertrophy (p = 0.004), it exacerbated proteinuria, decreased GFR (p < 0.05), and failed to reduce aortic NOX4. ANG did not affect tissue estrogen receptor expression, while E2 showed tissue-specific regulation of GPER and ERα. In this hypertensive OVX model, E2 failed to protect renal and vascular damage, emphasizing the importance of cardiovascular health at menopause when considering hormone therapy.