Developmental Programming of Cardiovascular Control: How Maternal Factors Influence the Health of the Adult Offspring

Abstract

There is accumulating evidence that hypertension is a symptom of underlying autonomic dysfunction, including aberrant stress responses. Before autonomic activity is examined in models of hypertension, the underlying connectivity that drives stress responses under physiological conditions must be further elucidated. In Chapter 3, we examined the afferent connectivity of the dorsomedial hypothalamus (DMH) by combining retrograde tracing and Fos immunohistochemistry following air jet stress. Stress-activated, DMH-projecting neurons were located predominantly in forebrain nuclei. Total numbers of these cells were modest, suggesting that their role may involve contextual modulation of the DMH output. In chapter 4, we demonstrated that gestational dofetilide programs hypertensive offspring with impaired stress habituation. Spectral analysis provided evidence of increased sympathetic vasomotor tone. Dofetilide shares its mechanism of action with several other drugs, thus, the results emphasise the need for further research into gestational drug use and potential programming effects. In chapter 5, we present the first evidence in rodents that advanced maternal age (AMA) programs offspring with lower blood pressure. Despite the proclivity for metabolic dysfunction, AMA offspring display reduced indices of sympathetic vasomotor tone and improved baroreflex. We hypothesise that the positive influence of maternal attentiveness programs improved blood pressure regulation. In chapter 6, we present preliminary data that show the DMH is influenced by reactive oxygen species. DMH microinjection of the O2 scavenger Tempol appeared to attenuate the sympathoexcitatory effects of a GABA(A) antagonist. Data from models of programmed hypertension indicate that the hypertensive phenotype is preceded by elevated oxidative stress. If ROS stimulates excitation of the DMH, this may explain why antioxidant intervention has proven to be an effective treatment in programmed hypertension.