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

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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.