Oxygen sensing mechanism(s) in fetal programming of salt-sensitive hypertension

盐敏感性高血压胎儿编程中的氧传感机制

• 批准号: 10923557
• 负责人: Ahmed Kolade OLOYO
• 金额: $ 2.59万
• 依托单位: COLLEGE OF MEDICINE, UNIVERSITY OF LAGOS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10923557
• 关键词: Adult; Adult Children; Animal Model; Animals; Antihypertensive Agents; Area; Blood Pressure; Blood Vessels; Data; Dependence; Disease; Environment; Event; Exposure to; Fetus; Functional disorder; Gene Activation; Genes; Genetic Transcription; HIF1A gene; Heme; Heritability; Homeostasis; Human; Hypertension; Hypoxia; Impairment; Individual; Injury to Kidney; Kidney; Laboratories; Life; Maternal Exposure; Mentors; Methods; Molecular; Nitric Oxide Synthase; Outcome Study; Oxidative Stress; Oxygen; Oxygenases; Pathway interactions; Perinatal; Perinatal Exposure; Peripheral Resistance; Play; Population; Predisposition; Pregnancy; Prevention; Procollagen-Proline Dioxygenase; Production; Proteins; Rattus; Regulation; Research; Resistance; Role; Series; Sodium Chloride; Sodium-Restricted Diet; Source; Stress; Testing; Testosterone; Tissues; Weaning; Western Blotting; bHLH-PAS factor HLF; blood pressure elevation; dietary salt; effective therapy; experimental study; fetal programming; genetic regulatory protein; high salt diet; human model; hypoxia inducible factor 1; improved; in utero; inhibitor; interest; normotensive; offspring; prevent; programs; response; salt sensitive hypertension; sensor; stem; therapeutic target; vascular bed

Abstract Heritability of saltsensitive hypertension and high susceptibility of offspring to maternal perinatal high salt diet (HSD) suggests that saltsensitive hypertension has its origin early in life. However, the mechanism(s) underlying the early origin of saltsensitive hypertension is not clear. Salt stress increases tissue demand for oxygen. In response, the tissue produces hypoxia inducible factor 1 alpha (HIF1α) which in turn activates its target antihypertensive genes (NOS2 and HO1) which consequently prevent blood pressure (BP) elevation in response to the salt stress. However, the activity of HIF1α is closely regulated by prolyl hydroxylase domaincontaining proteins 2 (PHD2). In saltsensitive hypertension, the regulatory function of PHD2 on HIF1α is impaired by HSD, consequently the ability of HIF1α to activate its target genes and prevent BP elevation in response to HSD is reduced. Likewise, impairment of the normal vasodilatory response to HSD is considered the initiator of the pressor response in saltsensitive hypertension. Considering the effect of HSD on tissue oxygen demand and the additive effect of the low oxygen tension environment of the in-utero life, we seek to investigate whether maternal exposure to perinatal HSD primes the fetus’ vascular oxygen sensors thereby, programming the offspring vascular beds to poorly respond to salt stress and develop saltsensitive hypertension in adult life. In our laboratory, we have used animal models to study the mechanisms that underlie the pathophysiology of saltsensitive hypertension – an interest that stemmed out of high percentage of saltsensitive hypertension in our population. In my US mentor’s laboratory, several cellular and molecular methods are used to investigate the mechanisms underlying saltsensitive hypertension and renal injury. Specifically, his research group has demonstrated the NOdependent regulation of HIF1α by PHD2 in salt induced hypertension and renal injury. However, it is unknown if PHD2, HIF1α, and its target antihypertensive genes are involved in the fetal programming of saltsensitive hypertension. Therefore, we hypothesized that exposure of dams to perinatal HSD dysregulates the vascular oxygen sensing mechanism(s) of the fetus, impairs vascular functions and causes hypertension in the offspring in adult life. We seek to demonstrate in the offspring: 1) that maternal exposure to perinatal HSD dysregulates the vascular oxygen sensing mechanism(s); 2) that dysregulation of the vascular oxygen sensing mechanism(s) impairs vascular function and causes hypertension; 3) that exposure of offspring to postweaning low salt diet reverses the effect of perinatal HSD on vascular oxygen sensing mechanism(s), vascular function and BP. The outcome of this study may open new areas for further experimentation and possible therapeutic targets for effective ways of preventing / controlling arterial BP and saltsensitive hypertension.

抽象的 盐敏感高血压的遗传力和后代对母亲围产期高盐饮食的高敏感性 （HSD）表明，盐敏的高血压起源于生命的早期。但是，基础机制 盐敏感高血压的早期起源尚不清楚。 盐胁迫增加了对氧的组织需求。作为响应，组织产生缺氧诱导因子1 α（HIF1α）又激活其靶标降压基因（NOS2和HO1） 防止血压（BP）响应盐胁迫。但是，HIF1α的活性紧密 由丙酰羟化酶结构域2（PHD2）调节。在盐敏感的高血压中 HSD损害了PHD2对HIF1α的调节功能，因此HIF1α激活其激活的能力 靶基因并防止响应HSD的BP升高。同样，正常的损害 对HSD的血管舒张反应被认为是盐敏Hypermension中压压反应的引发者。 考虑HSD对组织氧需求的影响以及低氧张力的附加效果 Utero生活的环境，我们试图调查产妇接触围产期HSD Primes是否暴露 因此，胎儿的血管氧气传感器，对后代血管床编程，以应对盐胁迫 并在成人生活中发展出盐敏感的高血压。 在我们的实验室中，我们使用动物模型研究了基于病理生理的机制 盐敏感高血压 - 这种兴趣是从高百分比的盐敏高血压中引起的 我们的人口。在我的美国心态中，使用了几种细胞和分子方法来研究 盐敏的高血压和肾脏损伤的基础机制。具体来说，他的研究小组有 在盐诱导的高血压和肾脏损伤中，通过PHD2对HIF1α的结节调节。 但是，尚不清楚PHD2，HIF1α及其靶标降压基因参与胎儿 盐敏高血压的编程。因此，我们假设大坝暴露于围产期HSD 胎儿的血管氧气传感机制失调，会损害血管功能和原因 成人后代的高血压。我们试图在后代中证明：1） 围产期HSD失调的血管氧感应机理（S）； 2）血管的失调 氧气感应机制会损害血管功能并引起高血压； 3）后代的暴露 在断奶后低盐饮食会逆转围产期HSD对血管氧气感应机制的影响， 血管功能和BP。 这项研究的结果可能会为进一步的实验和可能的治疗靶标开放新领域 预防 /控制动脉BP和盐敏感高血压的有效方法。