Oscar van der Have, Timothy J. Mead, Christian Westoo, Niccolo Peruzzi, Ayse C. Mutgan, Christian Norvik, Martin Bech, Andre Struglics, Konrad Hoetzenecker, Hans Brunnstrom, Gunilla Westergren-Thorsson, Grazyna Kwapiszewska, Suneel S. Apte, Karin Tran-Lundmark
Lund University and Skåne University Hospital. Cleveland Clinic. Ludwig Boltzmann Institute for Lung Vascular Research. Medical University Graz. Medical University of Vienna. Justus Liebig University.
Sweden, United States, Germany and Austria
Pulmonary Circulation
Pulm Circ 2023; 13:
DOI: 10.1002/pul2.12200
Abstract
Expansion of extracellular matrix occurs in all stages of pulmonary angiopathy associated with pulmonary arterial hypertension (PAH). In systemic arteries, dysregulation and accumulation of the large chondroitin-sulfate proteoglycan aggrecan is associated with swelling and disruption of vessel wall homeostasis. Whether aggrecan is present in pulmonary arteries, and its potential roles in PAH, has not been thoroughly investigated. Here, lung tissue from 11 patients with idiopathic PAH was imaged using synchrotron radiation phase-contrast microcomputed tomography (TOMCAT beamline, Swiss Light Source). Immunohistochemistry for aggrecan core protein in subsequently sectioned lung tissue demonstrated accumulation in PAH compared with failed donor lung controls. RNAscope in situ hybridization indicated ACAN expression in vascular endothelium and smooth muscle cells. Based on qualitative histological analysis, aggrecan localizes to cellular, rather than fibrotic or collagenous, lesions. Interestingly, ADAMTS15, a potential aggrecanase, was upregulated in pulmonary arteries in PAH. Aligning traditional histological analysis with three-dimensional renderings of pulmonary arteries from synchrotron imaging identified aggrecan in lumen-reducing lesions containing loose, cell-rich connective tissue, at sites of intrapulmonary bronchopulmonary shunting, and at sites of presumed elevated pulmonary blood pressure. Our findings suggest that ACAN expression may be an early response to injury in pulmonary angiopathy and supports recent work showing that dysregulation of aggrecan turnover is a hallmark of arterial adaptations to altered hemodynamics. Whether cause or effect, aggrecan and aggrecanase regulation in PAH are potential therapeutic targets.
Category
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes