Rhythmic Supplementation of 17β-Estradiol According to the Physiological Estrous Cycle: Effect on Blood Pressure in Female Ovariectomized Rats

Female Wistar-Kyoto rats (WKY) show a 4-day estrous cycle. The aim of this study was to examine the impact of 17 beta-estradiol supplementation every fourth day to ovariectomized rats-mimicking the physiological estrous cycle-on regulation of blood pressure. We monitored blood pressure telemetrically in intact females, ovariectomized (OVX), and ovariectomized WKY injected subcutaneously with 17 beta-estradiol (OVXE2) in a 4-day rhythm for 24 weeks. Blood pressure decreased both in intact females and OVXE2, whereas that of OVX persisted at constant levels. The underlying mechanisms studied include the nitric oxide pathway, the rennin-angiotensin system as well as the endothelin system. Serum and urinary nitrate/nitrite (NOx) as well as aortic eNOS decreased in OVX and were restored to normal in OVXE2. Conversely, caveolin-1 was higher in OVX than in intact females and OVXE2 while Hsp90 did not differ among groups. Plasma angiotensin II and aortic AT(1) receptor expression increased in OVX and were normalized in OVXE2. AT(2) receptor expression was regulated reciprocally. Serum endothelin-1 was significantly elevated in OVX and OVXE2. There was no difference in aortic ETA receptor expression between groups whereas ETB receptor expression was higher in intact females and OVXE2 than in OVX. The study suggests that supplementation of 17 beta-estradiol in female WKY according to the natural estrous cycle maintains the physiological blood pressure encompassing vasorelaxing and vasoconstricting pathways. The physiological estrous cycle should be kept in mind when cardiovascular data are to be collected/interpreted under estrogen supplementation.