Mast cell activation disrupts interactions between endothelial cells and pericytes during early life allergic asthma
Régis Joulia, … , Sejal Saglani, Clare M. Lloyd
Régis Joulia, … , Sejal Saglani, Clare M. Lloyd
Published March 15, 2024
Citation Information: J Clin Invest. 2024;134(6):e173676. https://doi.org/10.1172/JCI173676.
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Research Article Inflammation Vascular biology Article has an altmetric score of 28

Mast cell activation disrupts interactions between endothelial cells and pericytes during early life allergic asthma

Abstract

Allergic asthma generally starts during early life and is linked to substantial tissue remodeling and lung dysfunction. Although angiogenesis is a feature of the disrupted airway, the impact of allergic asthma on the pulmonary microcirculation during early life is unknown. Here, using quantitative imaging in precision-cut lung slices (PCLSs), we report that exposure of neonatal mice to house dust mite (HDM) extract disrupts endothelial cell/pericyte interactions in adventitial areas. Central to the blood vessel structure, the loss of pericyte coverage was driven by mast cell (MC) proteases, such as tryptase, that can induce pericyte retraction and loss of the critical adhesion molecule N-cadherin. Furthermore, spatial transcriptomics of pediatric asthmatic endobronchial biopsies suggests intense vascular stress and remodeling linked with increased expression of MC activation pathways in regions enriched in blood vessels. These data provide previously unappreciated insights into the pathophysiology of allergic asthma with potential long-term vascular defects.

Authors

Régis Joulia, Franz Puttur, Helen Stölting, William J. Traves, Lewis J. Entwistle, Anastasia Voitovich, Minerva Garcia Martín, May Al-Sahaf, Katie Bonner, Elizabeth Scotney, Philip L. Molyneaux, Richard J. Hewitt, Simone A. Walker, Laura Yates, Sejal Saglani, Clare M. Lloyd

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Figure 2

Repeated HDM exposure leads to loss of pericyte protrusions, reduced red blood cells, and hypoxic areas.

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Repeated HDM exposure leads to loss of pericyte protrusions, reduced red...
Neonate mice were exposed with PBS or HDM as indicated in Figure 1D. (A) 3D rendering of a PCLS section in PBS- and HDM-exposed mice 3 weeks after first inhalation showing CD31 (green, endothelial cells) and PDGFRβ (magenta, pericytes). Lower panels show pericyte cell body (red dots) and protrusion (magenta surface) analyses (see Supplemental Video 2). Scale bars: 30 μm (representative of 4 independent experiments). (B and C) PDGFRβ+ pericyte number per mm3 (B) and coverage (C, normalized to the total volume of CD31+ blood vessel) in the lung adventitia. n = 3–8 mice per group from 4 independent experiments. (D) Representative PCLS showing reduced red blood cell (Ter119+, purple) density in the microcirculation (CD31, green). Scale bars: 50 μm. Representative of 3 independent experiments. (E) Adventitial red blood cell density normalized to the total volume of the image. n = 3–4 mice per group from 3 independent experiments. (F) PCLS of HDM-exposed mice for 3 weeks exhibiting increased HIF-1α (purple) associated to the vasculature (CD31, green). Scale bars: 30 μm. Representative of 4 independent experiments. (G) Number of HIF-1α spots in adventitial region in PBS- and HDM-exposed mice (n = 4 mice per group). Data are represented as means ± SEM. *P < 0.05; **P < 0.01;***P < 0.001, 2-way ANOVA followed by Šidák’s post hoc test.