Mechanisms of hypertensive response sensitization and perinatal programming of hypertension

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PROJECT SUMMARY Work from our laboratory discovered that mild physiological and environmental challenges encountered earlier in adulthood produce sustained sensitization of the hypertensive response to subsequent hypertensinogenic challenges. Our recent studies indicate that the adult male offspring of dams with angiotensin II-produced gestational hypertension or eating a high-fat diet during the perinatal period also display sensitization of the hypertensive response. Accompanying this exacerbation of the hypertensive response is increased expression of components of the brain renin-angiotensin-aldosterone system, proinflammatory cytokines and activation of microglia in forebrain structures controlling sympathetic tone and blood pressure. Importantly, we find that administering a converting enzyme inhibitor to the sensitized offspring for six weeks between weaning and early adulthood abrogates gestational hypertension-induced sensitization of the hypertensive response. The present proposal builds on these findings with experiments that will determine: 1) the critical perinatal period when the hypertensive response can be sensitized by maternal gestational hypertension, 2) if maternal gestational hypertension alters mother-offspring behaviors to induce hypertensive response sensitization, 3) whether inhibitors of microglial activation and proinflammatory cytokines and other blockers of the renin-angiotensin- aldosterone system will reverse the sensitizing effects of maternal gestational hypertension and maternal perinatal high-fat diet intake, 4) why young females are protected against hypertensive response sensitization, 5) if maternal gestational hypertension or high-fat diet intake induces sensitized responses to identified hypertension risk factors related to dietary obesity, sodium intake and what factors are responsible of maintaining a sensitized response. This information will be obtained by using telemetry to measure blood pressure in freely moving rats and pharmacological methods to test mechanisms mediating hypertensive response sensitization. In addition molecular expression methods be used to characterize changes in mRNA and protein expression in key CNS regions controlling blood pressure. Completion of the proposed experiments will result in the delivery of important new information on how fetal programming results in increasing the likelihood of expression of enhanced hypertension later in life and measures that can be used to prevent it.