# The role of Alpha1-Adrenergic Receptors Promoter Methylation in Cerebral Autoregulation in Fetus

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2023 · $383,750

## Abstract

Summary: The ability of an organism to reduce the brain blood flow in response to sudden surges in systemic blood pressure
(BP) is known as cerebral autoregulation (CAR). In contrast to term neonates, preterm neonates are not able to reduce
cerebral blood flow (CBF) in response to increased systemic BP. In preterm neonates, this exposes fragile cerebral vessels
to a significantly increased blood flow at high pressure, leading to their rupture and brain damage. Our preliminary studies
demonstrate that near-term fetuses can constrict carotid arteries and reduce CBF when systemic BP rises; however, this
capability is not developed in the preterm fetus. We also observed that the constriction of carotid arteries to reduce CBF is
regulated by the adrenergic nervous system, specifically by the activities of alpha-1 adrenergic receptors (α1-ARs). These
receptors are expressed at a significantly lower number in preterm carotid arteries. Also, we observed that following the
removal of adrenergic control in the near-term fetus by severing the superior cervical ganglion (SCG) made them lose their
ability to reduce carotid blood flow (CaBF) to the brain with the rise in systemic BP. Thus, after the removal of SCG, both
preterm and near-term fetuses cannot reduce CBF following an increase in systemic BP. During ex-vivo experiments on
carotid segments, we observed that preterm arterial constriction in response to α1-ARs agonist was significantly lower than
those from near-term lambs. Thus, we concluded that reduced activities of α1-ARs play a fundamental role in regulating
CaBF with the rise in systemic BP. We also observed that the reduction in the activities of α1-ARs agonists in preterm
resulted from reduced expression of α1-ARs compared to those in near-term fetal lambs. Furthermore, we present evidence
that DNA hypermethylation reduces α1-ARs promoter activities by luciferase reporter assays and the involvement of histone
modifications. Thus, we will test the hypothesis that promoter DNA hypermethylation and histone modifications reduce the
expression and function of α1-AR subtypes (α1A-, α1B-, α1D) in the carotid arteries and play an essential role in the maturation
of cerebral autoregulation from preterm to term fetus. We will also collect data from both sexes (male versus female) to
identify sex-related changes. The studies will be conducted ex-vivo on isolated carotid arteries and in vivo in chronically
catheterized fetal sheep. 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 and histone modifications
on differential expression of α1-AR subtypes in carotid arteries. Aim 2: From preterm to term fetus, in a sex-specific manner,
we will determine the functional significance of differential α1-AR subtypes promoter methylation, histone modifications,
and gene expression on carotid artery contractility and blood flow...

## Key facts

- **NIH application ID:** 10657080
- **Project number:** 1R01HD109310-01A1
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Ravi Goyal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $383,750
- **Award type:** 1
- **Project period:** 2023-04-07 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10657080

## Citation

> US National Institutes of Health, RePORTER application 10657080, The role of Alpha1-Adrenergic Receptors Promoter Methylation in Cerebral Autoregulation in Fetus (1R01HD109310-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10657080. Licensed CC0.

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