# Interrogating distinct angiotensin type-1 and type-2 receptor containing brain circuits to understand and alleviate hypertension

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $375,597

## Abstract

Project Summary
Hypertension is a widespread health problem and a major risk factor for cardiovascular disease. Nearly one-
third of hypertensive patients suffer from drug-resistant hypertension; a condition associated with activation of
brain angiotensin receptors, enhanced sympathetic nervous system activity and elevated levels of circulating
vasopressin. The proposed experiments aim to identify neurons within the brain whose excitation or inhibition
is coupled to the pathophysiology underlying resistant hypertension. Our preliminary studies using mice with Cre
recombinase or green fluorescent protein directed by the genes for the angiotensin type 1a or type 2 receptors
(AT1R or AT2R) have provided intriguing insight. We have discovered that neurons in the organum vasculosum
of the lamina terminalis (OVLT) and median preoptic nucleus (MnPO) express AT1R or AT2R and send dense
excitatory projections to the paraventricular nucleus of the hypothalamus (PVN) and peri-PVN area, respectively.
Fascinatingly, optogenetic excitation of such AT1R neurons elicits robust (>40 mmHg) and sustained increases
in blood pressure, suggestive of sympathoexcitation and augmented vasopressin secretion. Within the
MnPO/OVLT the vast majority of AT2R(s) are NOT expressed on neurons that also synthesize AT1R, but rather,
are a separate population of neurons whose excitation may oppose the onset of hypertension. Consistent with
this interpretation, we recently discovered that pharmacological activation of AT2R facilitates GABAergic
mediated inhibition of vasopressin neurons and reduces systemic vasopressin and blood pressure. We have
developed the overall hypothesis that neurons within the MnPO/OVLT that express AT1R or AT2R project to the
PVN and peri-PVN area to coordinate sympathetic outflow and vasopressin secretion, and that the relative
activities of these neurons predict resistance or susceptibility to hypertension. To address this hypothesis, the
proposed studies combine Cre-LoxP technology, in vitro/in vivo optogenetics and classical systems physiology
with a mouse model of hypertension. Aim 1 will use optogenetics to probe the connection between neurons in
the MnPO/OVLT that express AT1R or AT2R and neurons in the PVN that express vasopressin. Sufficiency
and/or necessity of these connections will be determined for the increased sympathetic nervous system activity
and vasopressin secretion that promote neurogenic hypertension. Then, Aim 2 will use the Cre-loxP system to
delete AT1R and/or AT2R within the MnPO/OVLT and determine whether AT1R/AT2R signaling within these
brain nuclei contribute to the etiology of hypertension. Collectively, these experiments will determine whether
excitability and/or AT1R/AT2R signaling within this neural circuit can be altered to prevent high blood pressure.
These studies have the potential to uncover, at a detailed and mechanistic level, the neural circuits that are
compromised during hypertension and, in the long-term, may inf...

## Key facts

- **NIH application ID:** 9849328
- **Project number:** 5R01HL145028-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Annette Diane de Kloet
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $375,597
- **Award type:** 5
- **Project period:** 2019-01-15 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849328

## Citation

> US National Institutes of Health, RePORTER application 9849328, Interrogating distinct angiotensin type-1 and type-2 receptor containing brain circuits to understand and alleviate hypertension (5R01HL145028-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9849328. Licensed CC0.

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