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

• 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
• 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

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.

许多研究表明，母亲患有先兆子痫的个体的血压（BP）增加 （PE）。目前，PE的唯一治疗选择涉及提前交货。然而，在37周之前的出生导致 早产或低出生体重（LBW）也与后代BP增加有关。因此，有关键 需要为PE开发治疗干预措施，不仅可以改善孕产妇健康，还可以减轻胎儿 后代的生长限制和BP增加。降低子宫的特征良好模型 怀孕大鼠的灌注压力（RUPP）模仿PE的许多方面。亚历山大实验室报告 该BP在较早的雄性但女性LBW或宫内生长限制（IUGR）后代增加 成年。男性IUGR中BP的病因涉及增强的BP对血管紧张素II的敏感性（ANG ii）并增加肾脏氧化应激；而雌性IUGR升高的肾脏抗氧化酶活性 在成年时期是一种显着性的。初步数据表明雄性IUGR的AT1-AA升高 提出了增强的ANG II灵敏度的潜在介体，但肾脏氧化增加的病因学的病因 压力尚不清楚。线粒体压力在发育侮辱模型中肾脏中的作用也是 未知，但可能涉及microRNA。因此，该项目将使用IUGR的临床相关模型来测试 新的假设，即产妇干预改善胎盘灌注和减轻营养的转移 胎儿生长受损，导致IUGR后代中CV疾病的保护。此外，我们将测试 新的假设升高AT1-AA和microRNA介导的线粒体氧化应激是性别特异性的 在IUGR后代中BP增加的病因中。 AIM 1将测试母体治疗的假设 干预措施改善了子宫牙科灌注和减轻IUGR的营养和发展的转移 血压增加的起源在限制后代。目标2：将测试增加的假设 AT1-AA有助于男性成长受到限制的后代的血压的特定性别升高，并且 孕产妇治疗干预措施通过减少AT1-AA来减轻雄性IUGR的血压升高 活性并增强对血管紧张素II的敏感性。 AIM 3将检验肾脏氧化增加的假设 男性生长的压力受限制的后代起源于性别特异性引起的线粒体功能障碍 在成年期与氧化还原相关的microRNA的表达改变，而过早的衰老有助于 女性成长中的简历风险增加受到限制的后代。