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

van der Have, Oscar LU orcid ; Mead, Timothy J ; Westöö, Christian LU ; Peruzzi, Niccolò LU ; Mutgan, Ayse C LU ; Norvik, Christian LU ; Bech, Martin LU orcid ; Struglics, André LU ; Hoetzenecker, Konrad and Brunnström, Hans LU orcid , et al. (2023) In Pulmonary Circulation 13(1).
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Pulmonary Circulation
volume
13
issue
1
article number
e12200
publisher
SAGE Publications
external identifiers
  • scopus:85152393186
  • pmid:36824691
ISSN
2045-8932
DOI
10.1002/pul2.12200
language
English
LU publication?
yes
additional info
© 2023 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.
id
4dc0f180-8938-456d-a6b1-d5e1e31e2495
date added to LUP
2023-02-25 19:50:12
date last changed
2024-04-19 20:19:23
@article{4dc0f180-8938-456d-a6b1-d5e1e31e2495,
  abstract     = {{<p>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<br>
 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, <br>
 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 <br>
 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.<br>
 </p>}},
  author       = {{van der Have, Oscar and Mead, Timothy J and Westöö, Christian and Peruzzi, Niccolò and Mutgan, Ayse C and Norvik, Christian and Bech, Martin and Struglics, André and Hoetzenecker, Konrad and Brunnström, Hans and Westergren-Thorsson, Gunilla and Kwapiszewska, Grazyna and Apte, Suneel S and Tran-Lundmark, Karin}},
  issn         = {{2045-8932}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{1}},
  publisher    = {{SAGE Publications}},
  series       = {{Pulmonary Circulation}},
  title        = {{Aggrecan accumulates at sites of increased pulmonary arterial pressure in idiopathic pulmonary arterial hypertension}},
  url          = {{http://dx.doi.org/10.1002/pul2.12200}},
  doi          = {{10.1002/pul2.12200}},
  volume       = {{13}},
  year         = {{2023}},
}