# Neutrophils play a pivotal role in vascular aging

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $571,752

## Abstract

Abstract
Arterial stiffness is a hallmark of vascular aging and is related to increased cardiovascular disease events and
vascular dementias. Inflammatory damage and extracellular matrix remodeling have been proposed as the major
pathological causes of vascular injury and arterial stiffness. However, the molecular mechanisms that initiate
and propagate aging-related pathological changes in large blood vessels remain unclear. Here, we propose to
study the role of neutrophil elastase (NE), a neutrophil-specific protease, in initiating vascular leakage,
inflammation and fibrosis in aged mice both with and without obesity. Neutrophils are the most abundant
leukocytes, have a short lifespan, and play a critical role in initiating tissue damage and inflammation. Our data
demonstrated (1) that pulse wave velocity (PWV), the primary parameter of arterial stiffness, was decreased in
NE knockout (NEKO) mice compared to their wild-type littermates, and (2) that NEKO mice were resistant to
aging-related inflammation, fibrosis and calcification in the aorta. We also observed that NE has potent effects
on increasing vascular endothelial permeability and enhancing aortic smooth muscle cell fibrogenic and
osteogenic phenotypic switch. Further, NE regulates neutrophil proinflammatory phenotype by degrading
longevity regulator Sirtuin 1 (Sirt1). Based on our preliminary data, we hypothesize that pro-inflammatory
neutrophils interact with blood vessels, causing vascular damage and remodeling through the release of NE.
The latter contributes to the increased vascular permeability, fibrotic remodeling and calcification in the blood
vessels. Thus, inhibiting NE may lead to protective effects on aging-related vascular damage, fibrotic remodeling,
calcification, and subsequent arterial stiffness. The objective of this RO1 proposal is to explore how neutrophils
and NE regulate inflammatory remodeling in the arterial wall during the aging process with or without feeding of
an obesogenic diet. We will explore whether NE contributes to vascular aging by activating protease-activated
receptor 2 (PAR2) and epithelium sodium channel (ENaC) signaling pathways in vascular endothelial cells and
vascular smooth muscle cells with both in vitro and in vivo studies. Also, we will examine the role of the NE–Sirt1
signaling pathway in the regulation of neutrophil phenotype and aging-related vascular injury and remodeling in
mice. Finally, we will evaluate potential therapeutic effects of a selective NE inhibitor on aging-related arterial
stiffness in mice. Successful completion of this project will provide a novel therapeutic strategy for vascular aging
and related diseases.

## Key facts

- **NIH application ID:** 10813866
- **Project number:** 5R01HL168560-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Zhen Yue Jiang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $571,752
- **Award type:** 5
- **Project period:** 2023-03-22 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10813866

## Citation

> US National Institutes of Health, RePORTER application 10813866, Neutrophils play a pivotal role in vascular aging (5R01HL168560-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10813866. Licensed CC0.

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