Aggrecan accumulates at sites of increased pulmonary arterial pressure in idiopathic pulmonary arterial hypertension

作者：Oscar van der Have, Timothy J. Mead, Christian Westöö, Niccolò Peruzzi, Ayse Ceren Mutgan, Christian Norvik, Martin Bech, André Struglics, Konrad Höetzenecker, Hans Brunnström, Gunilla Westergren‐Thorsson, Grażyna Kwapiszewska, Suneel Apte, Karin Tran‐Lundmark · 发表于：Pulmonary Circulation · 年份：2023 · DOI：10.1002/pul2.12200 · 被引用次数：11 · 研究领域：Pulmonary Hypertension Research and Treatments、Proteoglycans and glycosaminoglycans research、Medical Imaging and Pathology Studies

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 t...