Mechanisms of hypertensive response sensitization and perinatal programming of hypertension

项目总结 我们实验室的工作发现，早先遇到的轻微生理和环境挑战 在成年期产生对随后的高血压激素反应的持续敏感化 挑战。我们最近的研究表明，患有血管紧张素II的成年雄鼠后代产生 妊娠期高血压或围产期食用高脂饮食也显示出对 高血压反应。伴随着高血压反应加剧的是表达的增加 脑肾素-血管紧张素-醛固酮系统的组成成分、促炎细胞因子和激活 前脑结构中的小胶质细胞控制交感神经张力和血压。重要的是，我们发现 从断奶到早期给致敏后代注射一种转换酶抑制剂，为期六周 成年期废除妊娠高血压引起的高血压反应的敏感化。现在 该提案建立在这些发现的基础上，并通过实验确定：1)关键的围产期 母亲妊娠高血压可使高血压反应敏感，2)如果母亲妊娠 高血压改变母子行为以诱导高血压反应敏感化，3)是否 小胶质细胞激活的抑制剂和促炎细胞因子以及其他肾素-血管紧张素受体阻滞剂- 醛固酮系统将逆转母体妊娠高血压综合征和母体妊娠的致敏作用 围产期高脂肪饮食摄入量，4)为什么年轻女性免受高血压反应敏感化的保护， 5)如果母亲妊娠期高血压或高脂饮食摄入导致对已识别的 与饮食肥胖、钠摄入量有关的高血压危险因素以及哪些因素负责维持 敏感的反应。这些信息将通过使用遥测来自由测量血压来获得 移动大鼠和药理学方法以测试介导高血压反应敏化的机制。 此外，分子表达方法还可以用来表征细胞中mRNA和蛋白质表达的变化 控制血压的中枢神经系统关键区域。完成拟议的实验将导致交付 关于胎儿程序化如何导致表达的可能性增加的重要新信息 晚年增强型高血压及其预防措施。

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.