Hypertension in Adult IUGR Offspring: Beneficial Effects of Perinatal Intervention

成年 IUGR 后代的高血压：围产期干预的有益效果

基本信息

批准号：
9903661
负责人：
Barbara T Alexander
金额：
$ 45.94万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903661
关键词：
Adult Age Aging Amino Acids Angiotensin II Antioxidants Attenuated Autoantibodies Autoimmune Diseases Birth Blood Circulation Blood Pressure Cardiovascular Diseases Cardiovascular system Carrier Proteins Cell Aging Chronic Chronic Disease Data Development Drug Delivery Systems Elastin Endothelin Etiology Event Exposure to Female Fetal Growth Fetal Growth Retardation Fetal Weight Fetus Growth Health Benefit Human Hypersensitivity Hypertension Individual Inflammation Inflammatory Intervention Ischemia Kidney Laboratories Life Low Birth Weight Infant Maternal Health Mediating Mediator of activation protein MicroRNAs Mitochondria Modeling Mothers Nutrient Oxidation-Reduction Oxidative Stress Pathogenesis Pathway interactions Peptides Perfusion Pharmacotherapy Phenotype Pre-Eclampsia Pregnancy Premature Birth Premature aging syndrome Rattus Reactive Oxygen Species Receptor, Angiotensin, Type 1 Reporting Risk Risk Factors Role Source Stabilizing Agents Stress TNF gene Teratogenic effects Testing Therapeutic Therapeutic Agents Therapeutic Intervention Uterus Weight Western World Woman antioxidant enzyme cardiovascular risk factor clinically relevant cytokine emerging adult enzyme activity fetal improved male middle age mitochondrial dysfunction normotensive novel offspring perinatal intervention polypeptide pregnant prenatal exposure pressure prevent programs protein expression pup receptor senescence sex tempol therapeutic target vector young adult

项目摘要

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.

大量研究表明，母亲患有先兆子痫的人的血压 (BP) 会升高（体育）。目前，PE 的唯一治疗选择是早期分娩。然而，37周前出生会导致早产或低出生体重（LBW）也与后代血压升高有关。因此，有一个关键的需要制定针对早泄的治疗干预措施，不仅可以改善孕产妇健康，还可以减轻胎儿的健康状况后代的生长受限和血压升高。特征明确的缩小子宫模型怀孕大鼠的灌注压 (RUPP) 与 PE 的许多方面相似。亚历山大实验室报告低出生体重或宫内生长受限 (IUGR) 后代的早期血压在男性而非女性中升高成年期。男性 IUGR 血压升高的病因涉及血压对血管紧张素 II (ANG) 的敏感性增强 II) 和肾脏氧化应激增加；而女性 IUGR 的肾脏抗氧化酶活性升高成年早期血压正常。初步数据表明 AT1-AA 在男性 IUGR 中升高表明 ANG II 敏感性增强的潜在介质，但肾氧化增加的病因学压力尚不清楚。肾脏中线粒体应激在发育损伤模型中的作用也被证实未知，但可能涉及 microRNA。因此，该项目将使用临床相关的 IUGR 模型来测试新的假设认为，母亲干预可以改善胎盘灌注和营养物质的转移，从而缓解胎儿生长受损，可保护 IUGR 后代免受心血管疾病的影响。此外，我们将测试 AT1-AA 升高和 microRNA 介导的线粒体氧化应激具有性别特异性的新假设 IUGR 后代血压升高的病因学。目标 1 将检验母亲治疗的假设干预措施改善子宫胎盘灌注和营养物质转移，减轻 IUGR 和发育障碍生长受限的后代血压升高的根源。目标 2：检验增加的假设 AT1-AA 导致雄性生长受限后代的性别特异性血压升高，并且母亲治疗干预通过减少 AT1-AA 来缓解男性 IUGR 血压的升高活性并增强对血管紧张素 II 的敏感性。目标 3 将检验肾氧化增加的假设雄性生长受限后代的应激源于性别特异性引起的线粒体功能障碍成年早期氧化还原相关 microRNA 的表达发生改变，并且过早衰老会导致女性生长受限的后代的心血管风险增加。