Hypertension in Adult IUGR Offspring: Beneficial Effects of Perinatal Intervention

大量研究表明，母亲患有先兆子痫的个体血压升高 （PE）。目前，PE的唯一治疗选择包括早期分娩。然而，在37周之前出生， 早产或低出生体重（LBW）也与后代血压升高有关。因此，有一个关键的 需要开发PE的治疗干预措施，不仅改善孕产妇健康，还减轻胎儿 生长受限和血压升高。子宫缩小的良好表征模型 妊娠大鼠的灌注压（RUPP）模拟PE的许多方面。亚历山大实验室报告说 在出生后早期，男性LBW或宫内生长受限（IUGR）后代的血压升高，而女性LBW或IUGR后代的血压升高， 成年男性IUGR血压升高的病因与血压对血管紧张素II（ANG）的敏感性增强有关 II）和肾脏氧化应激增加;而女性IUGR中肾脏抗氧化酶活性升高 在年轻人中血压正常。初步数据表明，AT1-AA在男性IUGR中升高 提示ANG II敏感性增强的潜在介质，但肾脏氧化性增加的病因是 压力尚不明确。线粒体应激在肾脏发育损伤模型中的作用也被研究。 未知，但可能涉及microRNA。因此，本项目将使用IUGR的临床相关模型来测试 母体干预改善胎盘灌注和营养转移的新假设 胎儿生长受损，导致IUGR后代免受CV疾病的影响。此外，我们将测试 AT1-AA和microRNA介导的线粒体氧化应激升高具有性别特异性的新假说 胎儿宫内发育迟缓后代血压升高的病因。目的1将测试假设，母亲治疗 干预措施改善子宫胎盘灌注和营养物质转移，减轻IUGR和发育 生长受限后代血压升高的原因。目标2：将检验假设， AT1-AA导致雄性生长受限后代的血压升高，且 母体治疗干预通过降低AT1-AA来减轻男性IUGR的血压升高 活性和对血管紧张素II的敏感性增强。目的3将检验增加肾脏氧化应激的假设， 雄性生长受限后代的应激来源于性特异性 在年轻的成年人中，氧化还原相关的microRNA表达改变，过早衰老有助于 女性生长受限后代的CV风险增加。

Numerous studies indicate blood pressure (BP) is increased in individuals whose mothers had preeclampsia (PE). Currently the only treatment option for PE involves early delivery. Yet, birth before 37 weeks resulting in preterm or low birth weight (LBW) is also associated with increased BP in the offspring. Thus, there is a critical need to develop therapeutic interventions for PE that not only improve maternal health but also mitigate fetal growth restriction and increased BP in the offspring. The well-characterized model of Reduced Uterine Perfusion Pressure (RUPP) in the pregnant rat mimics many facets of PE. The Alexander laboratory reports that BP is increased in male but not female LBW or intrauterine growth restricted (IUGR) offspring in early adulthood. The etiology of increased BP in male IUGR involves enhanced BP sensitivity to angiotensin II (ANG II) and increased renal oxidative stress; whereas, renal anti-oxidant enzyme activity elevated in female IUGR that are normotensive in young adulthood. Preliminary data indicate AT1-AA is elevated in male IUGR suggesting a potential mediator of enhanced ANG II sensitivity, but the etiology of increased renal oxidative stress is not yet clear. The role of mitochondrial stress in the kidney in models of developmental insult is also unknown but may involve microRNAs. Thus, this project will use a clinically relevant model of IUGR to test the novel hypothesis that maternal interventions improve placental perfusion and transfer of nutrients alleviating impaired fetal growth resulting in protection from CV disease in IUGR offspring. Furthermore, we will test the novel hypotheses that elevated AT1-AA and microRNA-mediated mitochondrial oxidative stress is sex-specific in the etiology of increased BP in IUGR offspring. Aim 1 will test the hypothesis that maternal therapeutic interventions improve uteroplacental perfusion and transfer of nutrients mitigating IUGR and the developmental origins of increased blood pressure in growth restricted offspring. Aim 2: will test the hypothesis that increased AT1-AA contributes to the sex-specific increase in blood pressure in male growth restricted offspring, and that maternal therapeutic interventions mitigate this increase in blood pressure in male IUGR by reducing AT1-AA activity and enhanced sensitivity to angiotensin II. Aim 3 will test the hypothesis that increased renal oxidative stress in male growth restricted offspring originates from mitochondrial dysfunction induced by sex-specific altered expression of redox-related microRNAs in young adulthood and that premature aging contributes to increased CV risk in female growth restricted offspring.