Intrauterine growth restriction induced via placental insufficiency programs a significant increase in blood pressure at 12 months of age in female growth-restricted rats that is associated with early cessation of estrous cyclicity indicative of premature reproductive senescence. In addition, female growth-restricted rats at 12 months of age exhibit a significant increase in circulating testosterone with no change in circulating estradiol. Testosterone is positively associated with blood pressure after menopause in women. Thus, we tested the hypothesis that androgen receptor blockade would abolish the significant increase in blood pressure that develops with age in female growth-restricted rats. Mean arterial pressure was measured in animals pretreated with and without the androgen receptor antagonist, flutamide (8 mg/kg/day, sc for 2 weeks). Flutamide abolished the significant increase in blood pressure in growth-restricted rats relative to control at 12 months of age. To examine the mechanism(s) by which androgens contribute to increased blood pressure in growth-restricted rats, blood pressure was assessed in rats untreated or treated with enalapril (250 mg/L for 2 weeks). Enalapril eliminated the increase in blood pressure in growth-restricted relative to vehicle- and flutamide-treated controls. Furthermore, the increase in medullary angiotensin type 1 receptor mRNA expression was abolished in flutamide-treated growth-restricted relative to untreated counterparts and controls; cortical angiotensin converting enzyme mRNA expression was reduced in flutamide-treated growth-restricted versus untreated counterparts. Thus, these data indicate that androgens, via activation of the renin angiotensin system, are important mediators of increased blood pressure that develops by 12 months of age in female growth-restricted rats.
Intrauterine growth restriction (IUGR) programs the development of hypertension associated with increased adiposity and accelerated reproductive senescence by 12 months of age in female IUGR rats. At 12 months of age the estradiol (E) to testosterone (T) ratio is shifted with E levels remaining similar whereas T levels are increased in female IUGR relative to control. Postmenopausal women have a higher prevalence of hypertension associated with increased adiposity. In addition, blood pressure (BP) is increased in association with increased serum T in postmenopausal women. Thus, we tested the hypothesis that chronic blockade of the androgen receptor would attenuate hypertension in female IUGR rats at 12 months of age. Rats were treated with flutamide (8mg/kg/day), an androgen receptor antagonist, or vehicle subcutaneously for two weeks. BP was measured in conscious, chronically catheterized rats. T levels were measured via radioimmunoassay. BP was increased in IUGR relative to control at 12 months of age (Δ15 mmHg, P<0.05); T levels were also elevated in IUGR vs. control (45.33±3.48 vs. 37.56 ±1.72 pg/ml; P<0.05). Flutamide decreased BP in IUGR relative to untreated IUGR (Δ7 mmHg) with no impact in control (Δ0 mmHg). Flutamide did not alter fat mass. Thus, these data indicate that T contributes to the etiology of hypertension that develops with age following IUGR in the female rat. NIH: HL074927, HL51971, P20GM104357, AHA GRNT19900004
Intrauterine growth restriction (IUGR) programs an increase in blood pressure associated with early reproductive senescence in female IUGR rats at 12 months of age. Serum testosterone (T) levels are increased in female IUGR rats at this age mimicking the hormonal milieu of postmenopausal women (PMW). Testosterone is positively associated with blood pressure in PMW. Thus, our laboratory previously reported that chronic blockade of the androgen receptor with flutamide abolished hypertension in female IUGR rats. However, the mechanism remained unclear. Activation the renin angiotensin system (RAS) may be important in the etiology of hypertension in PMW. Therefore, for this study we tested the hypothesis that activation of the vasoconstrictor arm of the RAS would be attenuated via chronic blockade of the androgen receptor in female IUGR rats. Following a two week treatment with flutamide (8mg/kg/day) or vehicle, kidneys were harvested and separated into cortex and medulla. Cortical RNA was isolated then converted into cDNA. Real‐time PCR was performed using Bio‐Rad SYBR Green Supermix and iCycler using primers for renin, androgen receptor, angiotensin converting enzyme (ACE) and angiotensin converting enzyme 2 (ACE2). Levels of mRNA expression are reported for cycle threshold method. Intrarenal renin mRNA expression was increased 2.5 fold (2.6±0.65 vs. 1±0.42, P<0.05) in renal cortex of IUGR vs. control kidneys. Following flutamide treatment, renin mRNA levels were normalized in IUGR vs. control (1.03±0.6 vs. 0.7±0.4). Androgen receptor and ACE expression were similar in vehicle control and IUGR rats; flutamide treatment had no further effect. There was a significant reduction in the ACE2 in vehicle treated IUGR relative to vehicle treated controls (0.84±0.12 vs. 1±0.11, P<0.05); however, flutamide treatment had no further effect on ACE2 expression. We previously reported that intrarenal ACE2 expression was increased in normotensive female IUGR offspring in young adulthood. Yet, we observe a reduction in intrarenal ACE2 expression with age in female IUGR rats. Thus, these data indicate that T may contribute to the etiology of hypertension in female IUGR rats via activation of the RAS. Since T causes activation of the RAS, targeting the androgen receptor could be a potential therapeutic intervention for postmenopausal hypertension.Support or Funding InformationNIH: HL074927, HL51971, P20GM104357, AHA: GRNT19900004, 15PRE24700010
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