Impact of Gonadectomy on Sex‐Selective Dysregulation of Cardiovascular Function Resulting From In UteroExposure to Dexamethasone

Abstract

Prenatal insults leading to increased fetal glucocorticoid exposure can sex‐selectively impact cardiovascular function in adulthood. In support of this, we have shown that when pregnant rat dams are treated with the glucocorticoid, dexamethasone (DEX), for the last 4 days of gestation, female‐specific changes resulting in enhanced pressor and heart rate (HR) responses to stress occur in adult offspring. Moreover, we demonstrated that females exposed to DEX in uteroshow altered autonomic function compared to vehicle‐exposed females. This is characterized by a reduced high frequency (HF) power component of heart rate variability (HRV) in DEX‐exposed rats, suggesting a lower reliance on parasympathetic drive. The present study evaluated the degree to which the sex‐specific changes in autonomically‐driven cardiovascular responses are due to activational effects of gonadal steroid hormones. Pregnant dams were administered DEX (0.4mg/kg per day, s.c.) or vehicle on gestation days 18‐21. This resulted in a significant reduction in birthweight in DEX‐exposed males and females. At 8 weeks, rats underwent a gonadectomy (GDX) or sham surgery, or remained intact, and at 10 weeks rats were instrumented with radiotelemetric transmitters for direct recording of arterial pressure, HR, and HRV in conscious, freely moving male and female rats. At 11‐12 weeks rats were placed in a restraint tube for 20 minutes, followed by a 3‐hour recovery period, to assess whether GDX alters the sex‐specific stress responses in DEX‐exposed offspring. Restraint‐stress testing was performed on diestrus in intact and sham females, and absence of cycling in GDX females was confirmed via cytological analysis. We demonstrate that intact females, but not males, that were exposed to DEX in utero exhibit an exaggerated pressor response to restraint, as compared to vehicle‐exposed females. We found that GDX did not alter stress‐responsive MAP in males regardless of prenatal treatment, suggesting testosterone does not play a role in acute cardiovascular stress responses in adult rats. In vehicle‐exposed females, when compared to intact, both sham and GDX surgery resulted in an exaggerated pressor response to restraint. However, in females that were prenatally exposed to DEX, there was no difference in the pressor response to restraint between intact, sham, and GDX rats. This suggests that the exaggerated pressor response observed in DEX females compared to males is not due to activational effects of estradiol. GDX was shown to have opposing effects on HRV in males and females, with no influence of prior DEX. In females, GDX resulted in a tendency toward reduced HF (p=0.065) and low frequency (LF, p=0.074) power component of HRV, whereas males showed a significant increase in HF (p=0.044) and a tendency toward increased LF (0.051). Taken together, activational effects of gonadal steroids appear to impact HRV, but not acute cardiovascular responses to stress. It may be that gonadal steroids act at an organizational level to mediate the sex difference observed in rats exposed to DEX in utero. Future studies to identify the mechanisms by which prenatal dexamethasone produce long‐term changes in cardiovascular function will be important for better understanding the sex‐specific consequences of prenatal programming over the lifespan.