Sex Differences in The Blood Pressure Response to Angiotensin (Ang) II in Aging Offspring of Polycystic Ovary Syndrome (PCOS) Rat Model

Abstract

Background PCOS, the most common endocrine disorder affecting women, is characterized by hyperandrogenemia, oligo-/anovulation, polycystic ovaries and elevated blood pressure (BP). In previous studies we found that adult male offspring of hyperandrogenemic female (HAF) rats, but not female offspring, have an exaggerated pressor response to Ang II. The present study tested the hypothesis that with aging, female offspring would also develop an exaggerated pressor response to Ang II. Methods PCOS was induced in Sprague Dawley (SD) females by implantation of 5α-dihydrotestosterone pellets (DHT; 7.5 mg/90 days, s.c.) at 4 weeks (wks) of age throughout life. HAF and control (Contr.) female rats (10-12 wks of age) were mated with SD males, and allowed to deliver and lactate. HAF and control male and female offspring (F1HAF and F1Contr., respectively) were left untreated (e.g. no DHT) and allowed to age. At 18-21 months of age, all offspring were implanted with radiotelemetry transmitters to measure BP (n = 4-5/group; 1 rat/litter/group). Following recovery for 2 wks, baseline mean arterial pressure (MAP) was measured for 9 days; then enalapril (25 mg/kg/d in drinking water) was given to all rats for 7 days. Along with enalapril, rats were also implanted with minipumps to deliver Ang II (50 ng/kg/min, s.c.) for 13 days. On the 8th day of Ang II, rats were given a 4 % salt diet. Females were continued on Ang II (50 ng/kg/min.) for an additional 9 days, and then minipumps were replaced to increase the dose of Ang II (200 ng/kg/min, s.c.) for 7 days, while continuing enalapril and 4% salt diet. Results Panel A: MAP was higher in males during baseline (B) than females. With enalapril (E), MAP decreased in all groups, but MAP in male F1HAF remained higher than in female F1HAF. Ang II (50 ng/kg/min) increased MAP to higher levels in male F1HAF than in male F1contr. on low salt. With high salt diet, by the end of 6 days, MAP was similar in both groups of male F1 rats. In contrast, low dose Ang II failed to increase MAP in female F1HAF compared to female F1contr. until rats received high salt diet, but MAP remained attenuated in female F1 HAF. Panel C: On high dose Ang II and high salt diet, MAP remained attenuated in aging female F1 HAF compared to female F1 contr. Conclusion These results indicate that with aging, male HAF offspring continue to have enhanced pressor sensitivity to low dose of Ang II, that is further exacerbated with high salt diet, whereas female HAF offspring have a blunted Ang II response compared to control offspring in the presence of high salt diet. The data may suggest that male PCOS offspring may develop increased risk for cardiovascular disease with aging.