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

摘要 盐敏感性高血压的遗传度及子代对母体围产期高盐饮食的高易感性 (HSD)表明盐敏感性高血压起源于生命早期。然而， 盐敏感性高血压的早期起源尚不清楚。 盐胁迫增加了组织对氧气的需求。作为回应，组织产生缺氧诱导因子1 HIF 1 α激活其靶向抗高血压基因（NOS 2和HO 1）， 防止血压（BP）升高，以应对盐的压力。然而，HIF 1 α的活性密切相关， 由脯氨酰羟化酶结构域蛋白2（PHD 2）调节。在盐敏感性高血压中， PHD 2对HIF 1 α的调节功能受到HSD的损害，因此HIF 1 α激活PHD 2的能力受到抑制。 靶向基因和防止响应HSD的BP升高。同样，正常的 对HSD的血管舒张反应被认为是盐敏感性高血压升压反应的起始。 考虑到HSD对组织需氧量的影响和低氧张力的叠加效应， 在子宫内生活的环境中，我们试图调查母体暴露于围产期HSD是否会引发子宫内的 胎儿的血管氧传感器，从而编程后代的血管床，以不良反应盐压力 并在成年后发展成盐敏感性高血压。 在我们的实验室中，我们已经使用动物模型来研究作为疾病病理生理学基础的机制。 盐敏感性高血压-对高盐敏感性高血压的兴趣， 我们的人口。在我的美国导师的实验室里，几种细胞和分子方法被用来研究 盐敏感性高血压和肾损伤的机制。具体来说，他的研究小组 证明了在盐诱导的高血压和肾损伤中PHD 2对HIF 1 α的NO依赖性调节。 然而，尚不清楚PHD 2、HIF 1 α及其靶向降压基因是否参与了胎儿高血压的发生。 盐敏感性高血压因此，我们假设母体暴露于围产期HSD 胎儿的血管氧传感机制失调，损害血管功能， 高血压在成年生活的后代。我们试图在后代中证明：1）母亲暴露于 围产期HSD使血管氧感受机制失调; 2）血管氧感受机制失调， 氧传感机制损害血管功能并导致高血压; 3）后代暴露于 断奶后低盐饮食逆转了围产期HSD对血管氧感受机制的影响， 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感性高血压的有效途径。

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.