# Pannexin 1 and sympathetic vasoconstriction

> **NIH NIH P01** · UNIVERSITY OF VIRGINIA · 2020 · $407,864

## Abstract

PROJECT 2 PROJECT SUMMARY
The fastest growing type of hypertension is sympathetically driven due to its close association with obesity, itself
reaching epidemic proportions. In this form of hypertension, the effect of sympathetic nerve (SN) activity – i.e.,
release of norepinephrine (NE) to bind α-adrenergic receptors (α-AR) on smooth muscle cells (SMC) on SMC –
is enhanced. NE is a potent vasoconstrictor and can strongly increase blood pressure. Thus, the smooth muscle
cells of resistance arteries is a major site for SN-driven hypertension. Our PPG has recently made important
discoveries in understanding the α−AR-mediated vasoconstriction pathway, which have forced us to re-think the
classical mechanism whereby sympathetic nerve induces SMC constriction. In resistance arteries, we found that
α-AR activation (and not other vasoconstriction receptor pathways) induced Pannexin 1 (Panx1) channel
opening on SMC to release ATP. This work identifies a key functional role for Panx1-derived ATP, and raises
new questions on the interaction between sympathetic nerve and SMCs. Furthermore, our PPG recently
discovered that the potent anti-hypertensive drug spironolactone acts directly on Panx1 channels to lower blood
pressure, independent of mineralocorticoid receptors. This work may have “unmasked” Panx1 as an important
additional component to the anti-hypertensive effects of spironolactone. Together, our published and preliminary
data provide the premise for the hypothesis tested in this proposal: Pannexin 1 links the sympathetic
nervous system to arterial function. We propose two aims to test this hypothesis. In Specific Aim 1, we
hypothesize that Pannexin 1 channels regulate sympathetic nerve control of peripheral resistance in
hypertension. This aim will incorporate models of sympathetic hypertension with Panx1 genetic knockout to
determine if Panx1 intervention can reverse high blood pressure. Additional Panx1 over-expression models and
new Panx1 pharmacological activators will help determine whether Panx1 can modulate blood pressure. In
Specific Aim 2, we ask further on the communication between sympathetic nerves and smooth muscle
cells. We will examine the purinergic signaling domain directly, by visualizing ATP release and stimulating
sympathetic nerves directly. A translational component will compare our findings to humans with and without
hypertension. The feasibility of accomplishing these aims is underscored by all proposed knockout mice being
in hand, an IRB in place for human samples, and the strong preliminary data. The integration of Project 2 with
other Projects on this P01 provides us with an opportunity to explore a novel pharmacological target for
sympathetic nerve-driven hypertension that could not have been achieved alone.

## Key facts

- **NIH application ID:** 9894840
- **Project number:** 5P01HL120840-07
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Brant E Isakson
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $407,864
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894840

## Citation

> US National Institutes of Health, RePORTER application 9894840, Pannexin 1 and sympathetic vasoconstriction (5P01HL120840-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9894840. Licensed CC0.

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