Abstract 136: Attenuation of Increased Blood Pressure by Chronic Estrogen Supplementation in Female IUGR Offspring at 12 months of Age is Associated With a Shift Towards ACE2

Abstract

Low birth weight ( LBW ) women exhibit an earlier age at menopause and a two-fold greater prevalence of hypertension in later life. In a model of LBW induced via placental insufficiency in the rat, female LBW rats develop an increase in blood pressure ( BP ) by 12 months of age. This is associated with persistent estrous that occurs 6 months prior to controls, indicative of early reproductive senescence. Although the underlying mechanisms are unknown, a shift in the hormonal milieu in addition to dysregulation of the renin angiotensin system ( RAS ) are potential contributors to the increase in BP that occurs in women after menopause. The vasoconstrictor arm of the RAS is implicated in increased BP; ACE2 counterbalances this shift towards increased BP. We previously reported that renal ACE2 expression is elevated in female LBW rats that are normotensive in young adulthood; an increase that is not present in female LBW rats in later life. Thus, this study tested the hypothesis that chronic 17β-estradiol ( E2 ) supplementation would reduce BP and shift the balance of the RAS in female LBW rats. Placebo or E2 pellets (1.5mg 17β-estradiol, 60-day release) were implanted at 12 months of age for 6 weeks followed by measurement of BP in conscious, chronically catheterized animals. Kidneys were collected for molecular analysis. BP was significantly increased in placebo-treated LBW relative to placebo-treated Control (134 vs 122 mmHg, respectively, p <0.05); an increase that was abolished by chronic E2 in LBW (116 mmHg, p <0.05). Using Real-Time PCR, cortical ACE2 mRNA expression did not differ between Control or LBW rats. Medullary ACE2 mRNA expression was significantly increased in placebo-treated LBW compared to placebo-treated Controls (1-fold increase; p <0.05). However, following chronic E2, medullary ACE2 mRNA expression was increased to a greater degree in chronic E2-treated LBW rats, almost two-fold higher, relative to chronic E2-treated Control. Therefore, these results suggest that E2 supplementation attenuates increased BP in female LBW rats in a manner that may involve a shift in the RAS towards ACE2 abundance suggesting that ACE2 via chronic E2 may be beneficial in the treatment of increased BP that occurs after reproductive senescence in LBW.