Estradiol replacement abolishes cardiovascular and intracranial changes induced by a high-fat diet in menopausal female rats.

The effects of β-estradiol (E2) on cardiovascular and intracranial responses, the renin-angiotensin-aldosterone system (RAAS) activity, and central nervous system inflammatory markers were investigated in an obesity-associated menopause model. Ovariectomized (OVX) or sham female adult Holtzman and Wistar rats were fed a high-fat diet (HFD; 46% and 60% fat from lipids) or standard diet (SD) (n = 5-6 animals/group) for 8 weeks. E2 was administered subcutaneously for 10 consecutive days. Blood pressure (BP) and intracranial pressure (ICP) responses were evaluated under baseline conditions and during pharmacological tests and acute ICP elevation. The HFD OVX group showed increases in BP (120 mmHg; p < 0.01), cerebral perfusion pressure (CPP: 116 mmHg; p < 0.01), P2/P1 ratio (1.17; p < 0.001), plasma renin concentration (48.9 pg/ml; p < 0.001), and elevated GFAP (229%; p < 0.001) and eNOS (165%; p < 0.001) in the brainstem. In the HFD OVX+E2 group, E2 reduced BP (104 mmHg; p < 0.01), CPP (99 mmHg; p < 0.01), P2/P1 ratio (0.96; p < 0.01), plasma renin (20.3 pg/ml; p < 0.001), GFAP (148%; p < 0.01) and eNOS (123%; p < 0.001). In the HFD OVX group, acute AT1 receptor blockade caused greater reductions in BP (75 mmHg; p < 0.05) and CPP (70 mmHg; p < 0.05), and abolished changes in ICP waveform morphology. In conclusion, obesity-associated menopause exacerbates alterations in cardiovascular and intracranial dynamics, that are attenuated by E2 replacement. Further pharmacokinetic, safety, and validation studies are necessary for clinical investigation.