Glucocorticoid-Mediated Programming of Cardiovascular and Autonomic Dysregulation in Adult Male and Female Rats

Abstract

The maternal environment programs placental development and produces changes in neuroendocrine, behavioral, metabolic, and cardiovascular function of offspring in adulthood. Specifically, environmental cues in the maternal environment resulting from conditions such as chronic stress, maternal immune activation, malnutrition, or maternal exposure to ethanol, nicotine, or excess glucocorticoids (GCs) are correlated with low birth weight and a predisposition for adult-onset disease, such as coronary artery disease, and an elevation in fetal GC exposure may be an underlying factor for this development. The mechanisms by which elevated GCs, in utero, program long-term changes in adult cardiovascular function, and how this development of future disease risk differs between sexes are not well understood. Autonomic dysregulation is associated with the development of cardiovascular diseases (CVDs). It may be that autonomic dysregulation of cardiovascular function is responsible for prenatal programming of cardiovascular dysregulation. The goal of the proposed research is to determine the mechanisms by which prenatal GC exposure produces sex-biased autonomic dysfunction in adult offspring. Naïve breeders were exposed to dexamethasone (DEX; 0.4mg/kg/day, s.c.) or vehicle (Veh) on gestation days 18-21. At 8-9 weeks offspring were instrumented with radiotelemetric devices for noninvasive measurement of mean arterial pressure (MAP), heart rate (HR), and heart rate variability (HRV). We hypothesized that excess exposure to GCs in utero will alter sympathovagal balance, and this impact will be greater in females than in males. To test this hypothesis, in Chapter 2, we examined the impact of the renin angiotensin system (RAS) on sex-selective changes in the prenatal programming of cardiovascular and autonomic function in response to acute stress exposure in adult animals. In Chapter 3, we evaluated the degree to which gonadal hormones influence stress-mediated cardiovascular responses in Veh or DEX-exposed offspring. In Chapter 4, we determined the extent to which changes in sympathetic (SYM) and parasympathetic (PS) activity underlie the prenatal GC-induced changes in CV function using pharmacological antagonists to block adrenergic (SYM) or cholinergic (PS) input. The main findings of this study are that (1) prenatal DEX results in exaggerated pressor and HR responses to acute restraint stress, and alters HRV in female offspring, but not males (Chapter 2). Angiotensin type 1 receptor antagonism attenuates this stress-responsive increase in female MAP and HR and normalizes HRV responses (Chapter 2). Gonadectomy in adult animals did not impact basal or stress-responsive cardiovascular function (Chapter 3). DEX produces a female-specific effect to shift sympathovagal balance from PS to SYM predominance (Chapter 4). These findings suggest that sex differences in autonomic balance and RAS activity may underlie the female-biased cardiovascular responses to stress in rats with prenatal GC exposure. The studies herein contribute to our understanding of the mechanisms by which sex-specific differences in prenatal GC-mediated programming of cardiovascular disease occur. Future studies designed to further elucidate the mechanisms by which prenatal perturbations sex-selectively program changes in offspring cardiovascular physiology are important for obtaining a better understanding of factors that influence the development of therapeutic approaches between sexes.