Abstract
Standard hormone therapy for menopausal women [conjugated equine estrogen (CEE) 0.625 mg] has been associated with increased risk of venous thrombosis. Regimens containing lower CEE dose (0.30 mg) have been clinically used to decrease side effects of supra-physiological doses of estrogen. In this study, we determined the effects of standard (SD) and low (LD) dose of CEE on venular function in ovariectomized (OVX) spontaneously hypertensive rats (SHR). Contractions to Angiotensin-II (Ang-II 10μM) in perfused mesenteric venular bed were markedly increased in OVX (21.5±1.3 mmHg) compared to Sham (14.7±1.1 mmHg, p<0.05). CEE-SD did not modify Ang-II responses in OVX, while CEE-LD restored Ang-II contraction to Sham levels. eNOS inhibition by L-NAME increased Ang-II contractions in Sham and CEE-LD, and was without effect in venules of OVX and CEE-SD. OVX decreased NO generation in association with diminished eNOS phosphorylation and increased O2- generation in the venular wall. CEE-LD reverted the deleterious effects of OVX. Although CEE-SD augmented eNOS phosphorylation in OVX, it was unable to increase NO levels, likely due to its inability to reduce O2-. Distinct effects by CEE-SD and CEE-LD are in parallel with the differential modulation of Ang-II (ATR) and estrogen (ER) receptors. Compared to Sham, CEE-LD increases AT2R while CEE-SD modifies ERβ expression in the venous bed. Interestingly, both CEE doses increased GPER in OVX. Our data suggest that estrogen dose is an important factor for venous function. While CEE-LD reverted deleterious effects of OVX, CEE-SD showed null effects despite its ability to increase eNOS activity.
- The American Society for Pharmacology and Experimental Therapeutics