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Pentastatin, a matrikine of the collagen IVα5, is a novel endogenous mediator of pulmonary endothelial dysfunction

Mutgan, Ayse Ceren LU orcid ; Jandl, Katharina ; Radic, Nemanja ; Valzano, Francesco ; Kolb, Dagmar ; Hoffmann, Julia ; Foris, Vasile ; Wilhelm, Jochen ; Boehm, Panja M and Hoetzenecker, Konrad , et al. (2023) In American journal of physiology. Cell physiology 325(5). p.1294-1312
Abstract

Deposition of basement membrane components, such as collagen IVα5, is associated with altered endothelial cell function in pulmonary hypertension. Collagen IVα5 harbors a functionally active fragment within its C-terminal noncollageneous (NC1) domain, called pentastatin, whose role in pulmonary endothelial cell behavior remains unknown. Here, we demonstrate that pentastatin serves as a mediator of pulmonary endothelial cell dysfunction, contributing to pulmonary hypertension. In vitro, treatment with pentastatin induced transcription of immediate early genes and proinflammatory cytokines and led to a functional loss of endothelial barrier integrity in pulmonary arterial endothelial cells. Mechanistically, pentastatin leads to... (More)

Deposition of basement membrane components, such as collagen IVα5, is associated with altered endothelial cell function in pulmonary hypertension. Collagen IVα5 harbors a functionally active fragment within its C-terminal noncollageneous (NC1) domain, called pentastatin, whose role in pulmonary endothelial cell behavior remains unknown. Here, we demonstrate that pentastatin serves as a mediator of pulmonary endothelial cell dysfunction, contributing to pulmonary hypertension. In vitro, treatment with pentastatin induced transcription of immediate early genes and proinflammatory cytokines and led to a functional loss of endothelial barrier integrity in pulmonary arterial endothelial cells. Mechanistically, pentastatin leads to β1-integrin subunit clustering and Rho/ROCK activation. Blockage of the β1-integrin subunit or the Rho/ROCK pathway partially attenuated the pentastatin-induced endothelial barrier disruption. Although pentastatin reduced the viability of endothelial cells, smooth muscle cell proliferation was induced. These effects on the pulmonary vascular cells were recapitulated ex vivo in the isolated-perfused lung model, where treatment with pentastatin-induced swelling of the endothelium accompanied by occasional endothelial cell apoptosis. This was reflected by increased vascular permeability and elevated pulmonary arterial pressure induced by pentastatin. This study identifies pentastatin as a mediator of endothelial cell dysfunction, which thus might contribute to the pathogenesis of pulmonary vascular disorders such as pulmonary hypertension.NEW & NOTEWORTHY This study is the first to show that pentastatin, the matrikine of the basement membrane (BM) collagen IVα5 polypeptide, triggers rapid pulmonary arterial endothelial cell barrier disruption, activation, and apoptosis in vitro and ex vivo. Mechanistically, pentastatin partially acts through binding to the β1-integrin subunit and the Rho/ROCK pathway. These findings are the first to link pentastatin to pulmonary endothelial dysfunction and, thus, suggest a major role for BM-matrikines in pulmonary vascular diseases such as pulmonary hypertension.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Hypertension, Pulmonary/chemically induced, Endothelial Cells/metabolism, Lung/metabolism, Endothelium/metabolism, Pulmonary Artery/metabolism, Collagen/metabolism, Integrins/metabolism
in
American journal of physiology. Cell physiology
volume
325
issue
5
pages
1294 - 1312
publisher
American Physiological Society
external identifiers
  • pmid:37694286
ISSN
1522-1563
DOI
10.1152/ajpcell.00391.2023
language
English
LU publication?
no
id
60c65c87-9e87-4174-a807-75caf7b9c7bf
date added to LUP
2025-03-20 13:54:31
date last changed
2025-04-04 14:38:28
@article{60c65c87-9e87-4174-a807-75caf7b9c7bf,
  abstract     = {{<p>Deposition of basement membrane components, such as collagen IVα5, is associated with altered endothelial cell function in pulmonary hypertension. Collagen IVα5 harbors a functionally active fragment within its C-terminal noncollageneous (NC1) domain, called pentastatin, whose role in pulmonary endothelial cell behavior remains unknown. Here, we demonstrate that pentastatin serves as a mediator of pulmonary endothelial cell dysfunction, contributing to pulmonary hypertension. In vitro, treatment with pentastatin induced transcription of immediate early genes and proinflammatory cytokines and led to a functional loss of endothelial barrier integrity in pulmonary arterial endothelial cells. Mechanistically, pentastatin leads to β1-integrin subunit clustering and Rho/ROCK activation. Blockage of the β1-integrin subunit or the Rho/ROCK pathway partially attenuated the pentastatin-induced endothelial barrier disruption. Although pentastatin reduced the viability of endothelial cells, smooth muscle cell proliferation was induced. These effects on the pulmonary vascular cells were recapitulated ex vivo in the isolated-perfused lung model, where treatment with pentastatin-induced swelling of the endothelium accompanied by occasional endothelial cell apoptosis. This was reflected by increased vascular permeability and elevated pulmonary arterial pressure induced by pentastatin. This study identifies pentastatin as a mediator of endothelial cell dysfunction, which thus might contribute to the pathogenesis of pulmonary vascular disorders such as pulmonary hypertension.NEW &amp; NOTEWORTHY This study is the first to show that pentastatin, the matrikine of the basement membrane (BM) collagen IVα5 polypeptide, triggers rapid pulmonary arterial endothelial cell barrier disruption, activation, and apoptosis in vitro and ex vivo. Mechanistically, pentastatin partially acts through binding to the β1-integrin subunit and the Rho/ROCK pathway. These findings are the first to link pentastatin to pulmonary endothelial dysfunction and, thus, suggest a major role for BM-matrikines in pulmonary vascular diseases such as pulmonary hypertension.</p>}},
  author       = {{Mutgan, Ayse Ceren and Jandl, Katharina and Radic, Nemanja and Valzano, Francesco and Kolb, Dagmar and Hoffmann, Julia and Foris, Vasile and Wilhelm, Jochen and Boehm, Panja M and Hoetzenecker, Konrad and Olschewski, Andrea and Olschewski, Horst and Heinemann, Akos and Wygrecka, Malgorzata and Marsh, Leigh M and Kwapiszewska, Grazyna}},
  issn         = {{1522-1563}},
  keywords     = {{Humans; Hypertension, Pulmonary/chemically induced; Endothelial Cells/metabolism; Lung/metabolism; Endothelium/metabolism; Pulmonary Artery/metabolism; Collagen/metabolism; Integrins/metabolism}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{5}},
  pages        = {{1294--1312}},
  publisher    = {{American Physiological Society}},
  series       = {{American journal of physiology. Cell physiology}},
  title        = {{Pentastatin, a matrikine of the collagen IVα5, is a novel endogenous mediator of pulmonary endothelial dysfunction}},
  url          = {{http://dx.doi.org/10.1152/ajpcell.00391.2023}},
  doi          = {{10.1152/ajpcell.00391.2023}},
  volume       = {{325}},
  year         = {{2023}},
}