# Neuroinflammation as a mediator of the exaggerated Piezo2 and Exercise Pressor Reflex in Peripheral Artery Disease

> **NIH NIH F31** · UNIVERSITY OF MINNESOTA · 2024 · $40,431

## Abstract

Project Summary
Peripheral artery disease (PAD) results in the progressive reduction of blood flow to peripheral body parts
including the lower limbs. The resulting ischemic muscle triggers an increased arterial pressure during lower limb
movements that is due to an exaggerated exercise pressor reflex (EPR). The EPR is a neural feedback
mechanism that leads to a physiological increase in blood pressure upon muscle contraction. When the EPR is
exaggerated in PAD, such that even low levels of muscle contraction (e.g., elicited by walking) cause abnormally
high blood pressure responses. This significantly contributes to the high risk of cardiovascular morbidity and
mortality in patients with PAD. Therefore, exercise, which has been shown to be beneficial for improving muscle
function and repair in patients with PAD cannot be safely prescribed to the patients. This emphasizes the need
for therapies that can normalize the EPR. The mechanically sensitive arm of the EPR mediates its exaggeration
in PAD, as has been shown by rodent femoral artery ligation (FAL), a well-established model of PAD. FAL
chronically sensitizes the mechanically sensitive receptors e.g., Piezo2, but the mechanism is unknown.
Preliminary studies from our lab show that Piezo2, in part, mediates the exaggerated EPR. The ischemic muscles
of patients and rodent models with PAD exhibit increased expression of pro-inflammatory genes and immune
cell infiltration. The effect that the resulting inflammatory cytokines from the ischemic muscle has on the muscle
mechanosensitive afferent neurons and their resident ion channels is unknown. Previous findings have reported
a signal transduction pathway that begins with an inflammatory mediator and culminates in the heightened
activity of a mechanosensitive channel in somatosensory neurons. Therefore, the hypothesis of this proposal
is that the pro-inflammatory signals from the ischemic muscle increase the expression and activity of
Piezo2 channels in mechanosensitive afferent neurons. To test this hypothesis, the proposed aims (Aim 1)
will determine the effect of proinflammatory mediators on the activity and expression of Piezo2 channel and other
mechanosensitive channels in mouse dorsal root ganglia (DRG) sensory neurons and hiPSC-derived sensory
neurons (hiPSC-SN). The effects of proinflammatory mediators in the absence of ischemia on Piezo2 and other
mechanosensitive channels’ expression and activity will also be investigated in vivo. To establish a definitive
cause-and-effect relationship between muscle inflammation and Piezo2 sensitization, the proposed experiments
involve macrophage depletion under ischemic conditions. The effects of this depletion on the activity and
expression of Piezo2 and other mechanosensitive channels in the DRG will be investigated. The resulting
findings will offer insights into the interplay between neural and immune responses in PAD, potentially leading
to novel therapeutic strategies to better managing the card...

## Key facts

- **NIH application ID:** 10995706
- **Project number:** 1F31HL175929-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Eunice Oribamise
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $40,431
- **Award type:** 1
- **Project period:** 2025-03-05 → 2030-03-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995706

## Citation

> US National Institutes of Health, RePORTER application 10995706, Neuroinflammation as a mediator of the exaggerated Piezo2 and Exercise Pressor Reflex in Peripheral Artery Disease (1F31HL175929-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10995706. Licensed CC0.

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