Sex-specific fetal programming of adult vascular dysfunction and hypertension

成人血管功能障碍和高血压的性别特异性胎儿编程

• 批准号: 8561661
• 负责人: SATHISH KUMAR
• 金额: $ 36.77万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-09 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8561661
• 关键词: Adult; Affect; African American; American; Androgens; Antiandrogen Therapy; Binding; Biological Assay; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Child; Clinical; Connexins; Development; Disease; Endothelium; Environment; Epidemiologic Studies; Event; Exhibits; Female; Fetus; Flutamide; Functional disorder; Gender; Hypertension; Impairment; Indium; Isoenzymes; Knowledge; Link; Measures; Mediating; Membrane Potentials; Mesentery; Messenger RNA; Modeling; Molecular; Molecular Profiling; Monitor; Muscle Contraction; Muscle Proteins; Nitric Oxide; Obesity; Pathogenesis; Pathology; Pathway interactions; Phenotype; Phosphorylation; Pre-Eclampsia; Pregnancy; Prevention strategy; Production; Protein Isoforms; Protein Kinase C; Proteins; Public Health; Rattus; Reporter; Reporting; Risk; Role; Series; Severities; Sex Characteristics; Signal Transduction; Smoking; Stimulus; Stress; Subcellular Fractions; Testing; Testosterone; Up-Regulation; Vascular Smooth Muscle; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Withdrawal; Woman; base; cardiovascular disorder risk; cardiovascular risk factor; clinically relevant; fetal programming; functional status; hypertension treatment; improved; in utero; insight; male; novel; offspring; postnatal; pregnant; prenatal; programs; promoter; public health relevance; research study; response; sex

DESCRIPTION (provided by applicant): Epidemiological studies show increased risk of cardiovascular (CV) diseases in children born to women with compromised pregnancies, such as in preeclampsia, PCOS, protein or energy restriction, obesity, stress, and smoking, but its pathogenesis remains incompletely understood. As one of the common factors observed in these pregnancy pathologies, elevated maternal testosterone (T) is likely to contribute to the fetal programming of CV disorders. Indeed, our recent studies demonstrate that elevated maternal T causes development of hypertensive phenotypes in rat offspring. To understand the mechanisms, 2 central hypotheses are proposed in this project. First, prenatal T induces sex-specific onset and severity of hypertension, and these hypertensive responses are mediated by postnatal increases in T levels. Second, increase in postnatal T induces hypertensive responses through sex-specific dysfunctions in vascular smooth muscle (VSM) protein kinase C (PKC) and endothelial EDHF/NO expression/function. To test these hypotheses, we propose a series of experiments in our established pregnant rat model and examine their offspring. Three specific aims are proposed: 1) Determine whether elevated maternal T programs offspring's hypertension, with more pronounced effect in males than females, and if postnatal T increase precedes hypertension onset. We will telemetrically monitor progressive changes in blood pressure (BP) and measure T levels to establish a relationship between onset and severity of hypertension and changes in postnatal T levels, mechanistically determining if postnatal T increase is the key contributing factor for BP increase. 2) Evaluate the sex-specific hypertensive mechanisms in VSM. We will examine the PKC isoenzyme expression profile in subcellular fractions, its phosphorylation status, and functional activity and examine mechanisms by which androgens regulate PKC expression by assessing binding of T to putative ARE in PKC promoter by ChiP and reporter assays. 3) Dissect the sex-specific mechanisms of impaired endothelial functions. We will examine the EDHF- and NO-mediated pathways and evaluate the mechanisms for impaired EDHF-mediated vasodilation by determining mRNA and protein levels of EDHF components SK3 and IK1 channels and connexins (CX37, CX40, and CX47), their subcellular localization, and functional activity using vascular reactivity and membrane potential studies. We will investigate the role of impaired NO-mediated vasodilator function by assessing the expression of eNOS, its activity, NO production, and signaling events. We expect that in utero T exposure will cause gender-specific hypertensive effects through upregulation of distinct vascular PKC isoenzymes and differential endothelial dysfunctions in the male and female vasculature, which may be regulated through postnatal changes in T levels. The results will provide a novel molecular basis to the understanding of fetal programming of adult CV dysfunction and improve our knowledge of sex differences in vascular dysfunction, providing an exciting opportunity to devise sex-specific strategies for prevention and treatment of hypertension.

描述（由申请人提供）：流行病学研究表明，患有妊娠受损的妇女所生的儿童患心血管（CV）疾病的风险增加，例如先兆子痫，PCOS，PCOS，蛋白质或能量限制或能量限制，肥胖，压力和吸烟，但其致病性仍未完全理解。作为在这些妊娠病理中观察到的常见因素之一，孕产妇睾丸激素（T）升高可能有助于CV疾病的胎儿编程。确实，我们最近的研究表明，孕产妇T的升高会导致大鼠后代的高血压表型的发展。为了理解这些机制，该项目提出了2个中心假设。首先，产前T会引起性别特异性的发作和高血压的严重程度，这些高血压反应是由T水平的产后增加介导的。其次，增加产后T的增加通过血管平滑肌（VSM）蛋白激酶C（PKC）和内皮EDHF/NO表达/功能引起性特异性功能障碍。为了检验这些假设，我们提出了一系列在我们已建立的怀孕大鼠模型中进行的实验，并检查其后代。提出了三个具体目的：1）确定升高的母体T计划后代的高血压是否比女性更明显的效果，并且如果产后T增加在前，则先于高血压发作。我们将远程监测血压（BP）的渐进性变化，并测量T水平，以建立高血压发作和严重程度之间的关系以及产后T水平的变化，从机械上确定产后T增加是否是BP增加的关键因素。 2）评估VSM中性别特定的高血压机制。我们将检查亚细胞级分中的PKC同酶表达谱，其磷酸化状态和功能活性，并检查雄激素通过评估T与假定的结合来调节PKC表达的机制，这是通过芯片和报告基因分析在PKC启动子中进行的。 3）剖析内皮功能受损的性别特异性机制。我们将检查EDHF-和NO介导的途径，并通过确定EDHF成分SK3和IK1通道和连接蛋白（CX37，CX40和CX47）的MRNA和蛋白质水平来评估EDHF介导的血管扩张受损的机制，并使用亚细胞的本地化进行了效果。我们将通过评估eNOS的表达，其活性，无生产和信号传导事件来研究受损的NO介导的血管扩张函数的作用。我们预计，在子宫内暴露会通过上调明显的血管PKC同工酶和雄性和雌性脉管系统的差异内皮功能障碍，从而引起性别特定的高血压作用，这可能会通过t水平的产后变化来调节。结果将为了解成人简历功能障碍的胎儿编程的理解提供新的分子基础，并提高我们对血管功能障碍性别差异的了解，从而为预防和治疗高血压的性别特定性策略提供了令人兴奋的机会。