# Mechanisms of acclimatization responses of fetal and adult cerebral artery alpha1 adrenergic receptor subtypes to long-term hypoxia

> **NIH NIH P01** · LOMA LINDA UNIVERSITY · 2020 · $120,328

## Abstract

Project Summary. The overall theme of this project is to understand at a deeper level the 
epigenetic-mediated signal transduction mechanisms by which the cerebrovasculature in the 
fetus and adult become acclimatized to high altitude, long-term hypoxia (LTH). This project is 
broadly based and vertically integrated using physiological, cellular, biochemical, and molecular 
approaches by four investigators trained in multiple disciplines and methodologies. Based on 
over two and one-half decades of intense investigation of the regulation of cerebrovascular 
reactivity, we shall test the hypothesis that acclimatization to long-term hypoxia is mediated, 
importantly and in part by epigenetic-mediated alpha1-adrenergic receptor (α1-AR) subtypes 
(α1A, α1B, - α1D), and their individual and unique roles in gene transcription. Our Specific Aims 
involve testing several associated hypotheses regarding both long-term hypoxia and 
developmental maturation including that of: What is the role of DNA methylation on transcription 
of alpha1-AR subtypes? What is the role of histone modifications (acetylation, methylation, and 
others) in α1-AR subtype-mediated transcription? What is the role of hypoxic-mediated 
microRNAs in this regard? What is the role of sympathetic innervation and α1-AR subtype in 
cerebral blood flow (CBF) regulation? What is the role of DNA methylation, histone acetylation, 
histone methylation, microRNA-mediated regulation of α1-AR subtype in CBF regulation as a 
consequence of LTH.?Scientifically the studies will augment our understanding of basic 
mechanisms whereby fetal and adult cerebral vessels acclimatize to LTH. They also will 
illustrate aspects of developmental regulation from fetus to adult. Clinically the studies relate to 
at least three critical problems. 1) For the fetus and newborn they relate to responses to 
prolonged hypoxia as occurs in women who live at high altitude, as well as those who smoke or 
are anemic, who have heart or lung disease; for the newborn altered cerebrovascular blood flow 
with intracerebral hemorrhage and pulmonary hypertension. 2) They also will contribute to 
understanding the epigenetic-mediated mechanisms of cardiovascular disorders and prenatal 
“programming” of adult disease. This includes the role of sympathetic innervation in this regard. 
3) In addition, they are relevant to understanding epigenetic-mediated mechanisms of diseases 
such as: Acute Mountain Sickness, Preeclampsia, and High Altitude Cerebral and Pulmonary 
Edema.

## Key facts

- **NIH application ID:** 9855056
- **Project number:** 5P01HD083132-05
- **Recipient organization:** LOMA LINDA UNIVERSITY
- **Principal Investigator:** Ravi Goyal
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $120,328
- **Award type:** 5
- **Project period:** — → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9855056

## Citation

> US National Institutes of Health, RePORTER application 9855056, Mechanisms of acclimatization responses of fetal and adult cerebral artery alpha1 adrenergic receptor subtypes to long-term hypoxia (5P01HD083132-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9855056. Licensed CC0.

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