Alpha Adrenergic Methylation and Developmental Maturation of Cerebral Autoregulation in Ovine Preterm Fetus

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Summary: Preterm infants have a significantly higher incidence of brain damage as a consequence of immature cerebral blood flow (CBF) autoregulation. In contrast to term neonates, preterm neonates are not able to reduce CBF in response to increased systemic BP. In preterm neonates, exposure of fragile cerebral vessels to an increased amount of blood flow at elevated systemic pressure leads to their rupture and brain damage. Our preliminary studies demonstrate that near-term fetuses and term-newborn lambs can constrict carotid arteries and reduce CBF when systemic BP rises; however, this capability is not developed in the preterm fetus. Also, we observed that following the removal of sympathetic control in the near-term fetus by severing the superior cervical ganglion made them lose their ability to restrict carotid blood flow to the brain with the rise in systemic BP. We also observed that the constriction of carotid arteries to reduce CBF is regulated by the sympathetic nervous system, specifically by the activity of alpha-1 adrenergic receptors (α1-ARs). These receptors are expressed at a significantly lower number in preterm carotid arteries. Thus, we concluded that reduced activity of α1-ARs plays a fundamental role in regulating carotid blood flow with the rise in systemic BP. Furthermore, we present evidence that differential DNA methylation regulates α1-ARs promoter activity and expression. Thus, we will test the hypothesis that DNA methylation and demethylation regulate the expression and function of α1-AR subtypes (α1A-, α1B-, α1D) in the carotid arteries and play a crucial role in the maturation of CAR from preterm to term fetus. We will collect data from both sexes to identify any sex-related changes. The studies will be conducted in-vivo in chronically catheterized fetal sheep and ex-vivo on isolated carotid arteries. The hypothesis will be tested with two specific aims. Aim 1: From preterm to term fetus in a sex-specific manner, we will conduct an in-depth mechanistic analysis of promoter DNA methylation on differential expression of α1-AR subtypes in carotid arteries. Aim 2: In a sex-specific manner, we will determine the functional significance of differential α1-AR subtypes promoter methylation and expression on carotid artery contractility and blood flow. The measurements will be conducted in real-time, in-vivo, with in-utero fetal maturation. This will provide valuable information regarding the role of α1-AR subtypes and the epigenetic mechanisms involved in the maturation of CAR.