B33-19 Spatially Dysregulated Mechanical Stress and Piezo1 Upregulation in Peripheral Lung Endothelium of Asthmatic Patients

Abstract

Asthma is a common respiratory disease, but whether its symptom exacerbation is related to mechanical forces and the underlying mechanisms remain incompletely understood. This study aimed to investigate the role of region-specific vascular mechanosignaling transduction in the pathogenesis of asthma. Through single-nucleus RNA sequencing analysis, we found that mechanical force-related signaling was significantly enhanced in the lung tissues of asthma patients, particularly prominent in vascular endothelial cells. Single-photon emission computed tomography (SPECT) of asthma patients further revealed markedly reduced blood perfusion in the lungs, especially in the peripheral regions, showing abnormal spatial distribution. Integrated single-cell and single-nucleus RNA sequencing analysis of surgically resected peripheral and central lung tissue samples demonstrated selective enrichment of mechanical stress-related signaling pathways in endothelial cells from the peripheral lung regions of asthma patients. Moreover, the mechanosensitive ion channel PIEZO1 showed significant and region-specific upregulation in peripheral lung endothelial cells of asthma patients, which was confirmed at the protein level by immunohistochemistry. To establish causality, we employed an OVA-induced allergic asthma mouse model and found that conditional knockout of endothelial-specific Piezo1 significantly alleviated nighttime exacerbation of asthma phenotypes, specifically reducing airway hyperresponsiveness, eosinophilic inflammation, and type 2 cytokine levels during the active phase. In summary, this study reveals a novel spatial pathological mechanism in asthma: dysregulated mechanical forces in the peripheral pulmonary vascular system drive selective upregulation of endothelial PIEZO1, playing a key role in asthma exacerbation and offering a potential therapeutic target.

This abstract is funded by: None