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Basement membrane remodeling controls endothelial function in idiopathic pulmonary arterial hypertension

Jandl, Katharina ; Marsh, Leigh M. ; Hoffmann, Julia ; Mutgan, Ayse Ceren LU orcid ; Baum, Oliver ; Bloch, Wilhelm ; Thekkekara-Puthenparampil, Helene ; Kolb, Dagmar ; Sinn, Katharina and Klepetko, Walter , et al. (2020) In American Journal of Respiratory Cell and Molecular Biology 63(1). p.104-117
Abstract

The extracellular matrix (ECM) increasingly emerges as an active driver in several diseases, including idiopathic pulmonary arterial hypertension (IPAH). The basement membrane (BM) is a specialized class of ECM proteins. In pulmonary arteries, the BM is in close contact and direct proximity to vascular cells, including endothelial cells. So far, the role of the BM has remained underinvestigated in IPAH. Here, we aimed to shed light on the involvement of the BM in IPAH, by addressing its structure, composition, and function. On an ultrastructural level, we observed a marked increase in BM thickness in IPAH pulmonary vessels. BM composition was distinct in small and large vessels and altered in IPAH. Proteoglycans were mostly responsible... (More)

The extracellular matrix (ECM) increasingly emerges as an active driver in several diseases, including idiopathic pulmonary arterial hypertension (IPAH). The basement membrane (BM) is a specialized class of ECM proteins. In pulmonary arteries, the BM is in close contact and direct proximity to vascular cells, including endothelial cells. So far, the role of the BM has remained underinvestigated in IPAH. Here, we aimed to shed light on the involvement of the BM in IPAH, by addressing its structure, composition, and function. On an ultrastructural level, we observed a marked increase in BM thickness in IPAH pulmonary vessels. BM composition was distinct in small and large vessels and altered in IPAH. Proteoglycans were mostly responsible for distinction between smaller and larger vessels, whereas BM collagens and laminins were more abundantly expressed in IPAH. Type IV collagen and laminin both strengthened endothelial barrier integrity. However, only type IV collagen concentration dependently increased cell adhesion of both donor and IPAH-derived pulmonary arterial endothelial cells (PAECs) and induced nuclear translocation of mechanosensitive transcriptional coactivator of the hippo pathway YAP (Yes-activated protein). On the other hand, laminin caused cytoplasmic retention of YAP in IPAH PAECs. Accordingly, silencing of COL4A5 and LAMC1, respectively, differentially affected tight junction formation and barrier integrity in both donor and IPAH PAECs. Collectively, our results highlight the importance of a well-maintained BM homeostasis. By linking changes inBMstructure and composition to altered endothelial cell function, we here suggest an active involvement of the BM in IPAH pathogenesis.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Barrier function, Extracellular matrix, Laminin, Type IV collagen, Vascular remodeling
in
American Journal of Respiratory Cell and Molecular Biology
volume
63
issue
1
pages
104 - 117
publisher
American Thoracic Society
external identifiers
  • scopus:85087469845
  • pmid:32160015
ISSN
1044-1549
DOI
10.1165/rcmb.2019-0303OC
language
English
LU publication?
no
additional info
Publisher Copyright: Copyright © 2020 by the American Thoracic Society.
id
93b2a503-b3a9-400f-975c-f9cbc7787193
date added to LUP
2025-03-20 13:59:10
date last changed
2025-06-27 05:26:25
@article{93b2a503-b3a9-400f-975c-f9cbc7787193,
  abstract     = {{<p>The extracellular matrix (ECM) increasingly emerges as an active driver in several diseases, including idiopathic pulmonary arterial hypertension (IPAH). The basement membrane (BM) is a specialized class of ECM proteins. In pulmonary arteries, the BM is in close contact and direct proximity to vascular cells, including endothelial cells. So far, the role of the BM has remained underinvestigated in IPAH. Here, we aimed to shed light on the involvement of the BM in IPAH, by addressing its structure, composition, and function. On an ultrastructural level, we observed a marked increase in BM thickness in IPAH pulmonary vessels. BM composition was distinct in small and large vessels and altered in IPAH. Proteoglycans were mostly responsible for distinction between smaller and larger vessels, whereas BM collagens and laminins were more abundantly expressed in IPAH. Type IV collagen and laminin both strengthened endothelial barrier integrity. However, only type IV collagen concentration dependently increased cell adhesion of both donor and IPAH-derived pulmonary arterial endothelial cells (PAECs) and induced nuclear translocation of mechanosensitive transcriptional coactivator of the hippo pathway YAP (Yes-activated protein). On the other hand, laminin caused cytoplasmic retention of YAP in IPAH PAECs. Accordingly, silencing of COL4A5 and LAMC1, respectively, differentially affected tight junction formation and barrier integrity in both donor and IPAH PAECs. Collectively, our results highlight the importance of a well-maintained BM homeostasis. By linking changes inBMstructure and composition to altered endothelial cell function, we here suggest an active involvement of the BM in IPAH pathogenesis.</p>}},
  author       = {{Jandl, Katharina and Marsh, Leigh M. and Hoffmann, Julia and Mutgan, Ayse Ceren and Baum, Oliver and Bloch, Wilhelm and Thekkekara-Puthenparampil, Helene and Kolb, Dagmar and Sinn, Katharina and Klepetko, Walter and Heinemann, Akos and Olschewski, Andrea and Olschewski, Horst and Kwapiszewska, Grazyna}},
  issn         = {{1044-1549}},
  keywords     = {{Barrier function; Extracellular matrix; Laminin; Type IV collagen; Vascular remodeling}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{104--117}},
  publisher    = {{American Thoracic Society}},
  series       = {{American Journal of Respiratory Cell and Molecular Biology}},
  title        = {{Basement membrane remodeling controls endothelial function in idiopathic pulmonary arterial hypertension}},
  url          = {{http://dx.doi.org/10.1165/rcmb.2019-0303OC}},
  doi          = {{10.1165/rcmb.2019-0303OC}},
  volume       = {{63}},
  year         = {{2020}},
}