# Renewal: Pannexin-1 signaling in abdominal aortic aneurysms

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2024 · $694,879

## Abstract

PROJECT SUMMARY
Abdominal aortic aneurysms (AAA) formation and subsequent aortic rupture can lead to sudden death and is a
significant clinical problem with no currently known medical treatments available. The hallmarks of patient AAA
include thrombus formation and cell death mechanisms such as apoptosis and neutrophil extracellular traps
(NETs). The clearance of dead cell debris is mediated via the process of efferocytosis, by which apoptotic
tissue is recognized for engulfment by professional phagocytes (e.g., macrophages) and non-professional
phagocytes (e.g., endothelial cells; ECs), and remains to be elucidated in the pathogenesis of AAA. Thus, our
hypothesis focuses on the dysregulation of inflammation-resolution pathways that lead to to defective
efferocytosis and promote chronic aortic tissue inflammation and vascular remodeling. Our recent study has
demonstrated a critical role orchestrated by EC-dependent pannexin-1 (Panx1) channels in causing aortic
inflammation and AAA formation. The scientific premise of this proposal focuses on the dysregulation of EC-
mediated efferocytosis causing an imbalance of inflammation-resolution via Panx1 activation in AAA
progression. Therefore, the central hypothesis in this proposal is that EC efferocytosis is dysregulated due to
cleavage of MerTK, a cell surface tyrosine kinase receptor that recognizes apoptotic cells, leading to
accumulation of dead cell debris and thrombus formation. Second, our mechanistic studies will dissect the
dynamic communication between ECs and macrophages, involving defective EC-mediated efferocytosis
leading to excessive iron-mediated cell death (ferroptosis) in macrophages, that collectively feedbacks to
cause Panx1 activation and an chronic inflammatory loop. Our supportive data demonstrates that resolution of
aortic inflammation is associated with increased EC-dependent MerTK expression and efferocytosis of
neutrophils. Furthermore, defective EC-mediated efferocytosis exacerbates ferroptosis in macrophages (via
SLC7A11 and Nrf2-signaling) that feedbacks to cause EC-Panx1 activation and eATP release. Collectively, our
results suggest that dysregulation of EC-mediated efferocytosis and macrophage-dependent ferroptosis
creates a break in the inflammation-resolution process during AAA formation and aortic rupture. We will
delineate the proposed studies using the murine elastase-treatment AAA and our innovative aortic rupture
model, as well as by analysis of human AAA tissue from our biorepository. Using novel inducible cell-specific
genetic knockout mice such as Cdh5Cre-ERT2/MerTKfl/fl, MerTKCR (cleavage-resistant), and Cx3CR1Cre-
ERT2/SLC7A11fl/fl mice, we will delineate the previously unknown mechanisms of dysregulated efferocytosis and
ferroptosis in activation of Panx1 channels during AAA formation. Our studies will provide novel insight into
mechanisms of molecular signaling interactions between ECs and macrophages to define the inflammatory
loop between efferocytosis/f...

## Key facts

- **NIH application ID:** 10840414
- **Project number:** 5R01HL138931-06
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Ashish Kumar Sharma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $694,879
- **Award type:** 5
- **Project period:** 2018-07-09 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840414

## Citation

> US National Institutes of Health, RePORTER application 10840414, Renewal: Pannexin-1 signaling in abdominal aortic aneurysms (5R01HL138931-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10840414. Licensed CC0.

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