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

摘要 盐敏性高血压的遗传度和子代对母体围产期高盐饮食的易感性 (HSD)表明盐敏感型高血压有其早期生活的起源。然而，背后的机制(S) 盐敏感型高血压的早期起源尚不清楚。 盐胁迫会增加组织对氧气的需求。作为回应，组织产生缺氧诱导因子1 α(HIF1α)，进而激活其目标降压基因(NOS2和HO1)，从而 防止血压(BP)升高，以应对盐胁迫。然而，hif1α的活性密切相关。 受含脯氨酸羟基酶结构域的蛋白2(PHD2)调控。在盐敏性高血压中， HSD使PHD_2对HIF_1α的调节功能减弱，从而使HIF_1α激活其 靶向基因和防止血压升高对HSD的反应降低。同样，正常人的损害 对HSD的血管扩张反应被认为是盐敏感型高血压升压反应的始动因素。 考虑HSD对组织需氧量的影响和低氧分压的相加效应 ，我们试图调查母亲在围产期接触HSD是否会导致 因此，胎儿的血管氧气感应器对后代的血管床进行编程，使其对盐胁迫的反应不佳 并在成年后患上盐敏感型高血压。 在我们的实验室里，我们使用动物模型来研究糖尿病的病理生理学基础。 盐敏感型高血压--这一兴趣源于#年盐敏感型高血压的高比例 我们的人口。在我的美国导师的实验室里，使用了几种细胞和分子方法来研究 盐敏感型高血压和肾脏损伤的机制。具体地说，他的研究小组 证实了在盐诱导的高血压和肾损伤中，PHD2对HIF1α的调节具有NO依赖性。 然而，目前尚不清楚phd2、hif1、α及其靶基因是否与胎儿的高血压有关。 盐敏性高血压的程序设计。因此，我们假设母体暴露于围产期HSD 胎儿血管氧感机制失调(S)，损害血管功能及原因 成年后后代的高血压。我们试图在后代中证明：1)母体接触 围产期HSD调节血管氧感受机制失调(S)；2)血管调节失调 氧气感应机制(S)损害血管功能并导致高血压；3)子代暴露 断奶后低盐饮食逆转围产期高盐饮食对血管氧感受机制的影响(S)， 血管功能和血压。 这项研究的结果可能为进一步的实验和可能的治疗靶点开辟新的领域。 预防/控制动脉血压和盐敏性高血压的有效方法。

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.