TY - JOUR
T1 - Aggrecan accumulates at sites of increased pulmonary arterial pressure in idiopathic pulmonary arterial hypertension
AU - van der Have, Oscar
AU - Mead, Timothy J
AU - Westöö, Christian
AU - Peruzzi, Niccolò
AU - Mutgan, Ayse C
AU - Norvik, Christian
AU - Bech, Martin
AU - Struglics, André
AU - Hoetzenecker, Konrad
AU - Brunnström, Hans
AU - Westergren-Thorsson, Gunilla
AU - Kwapiszewska, Grazyna
AU - Apte, Suneel S
AU - Tran-Lundmark, Karin
N1 - © 2023 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.
PY - 2023/2/3
Y1 - 2023/2/3
N2 - 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.
AB - 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.
U2 - 10.1002/pul2.12200
DO - 10.1002/pul2.12200
M3 - Article
C2 - 36824691
SN - 2045-8932
VL - 13
JO - Pulmonary Circulation
JF - Pulmonary Circulation
IS - 1
M1 - e12200
ER -