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Localization, Proteolytic Processing, and Binding Partners of Versican Isoforms in Vascular Lesions of Pulmonary Arterial Hypertension

Westöö, Christian LU ; Mutgan, Ayse Ceren LU orcid ; van der Have, Oscar LU orcid ; Mead, Timothy J ; Ahmed, Salaheldin LU orcid ; Lampei, Elna LU ; Koch, Christopher D ; Norvik, Christian LU ; Aspberg, Anders LU orcid and Bech, Martin LU orcid , et al. (2025) In The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society
Abstract

Pulmonary arterial hypertension (PAH) is a lethal condition where expansion of the vascular extracellular matrix contributes to increased pulmonary vascular resistance. Versican, a chondroitin sulfate proteoglycan, is known to accumulate in vascular lesions of PAH and hyaluronan and tenascin-C, binding partners of versican, are elevated in PAH. The specific distribution and localization of versican isoforms, their cleavage products, and binding partners in vascular lesions of PAH had not been studied previously. Versican has five distinct isoforms, V0-V4, identified by the arrangement of its chondroitin-sulfate attachment regions, GAGα and GAGβ. Here, tissue from idiopathic PAH was imaged with synchrotron-based phase-contrast micro-CT... (More)

Pulmonary arterial hypertension (PAH) is a lethal condition where expansion of the vascular extracellular matrix contributes to increased pulmonary vascular resistance. Versican, a chondroitin sulfate proteoglycan, is known to accumulate in vascular lesions of PAH and hyaluronan and tenascin-C, binding partners of versican, are elevated in PAH. The specific distribution and localization of versican isoforms, their cleavage products, and binding partners in vascular lesions of PAH had not been studied previously. Versican has five distinct isoforms, V0-V4, identified by the arrangement of its chondroitin-sulfate attachment regions, GAGα and GAGβ. Here, tissue from idiopathic PAH was imaged with synchrotron-based phase-contrast micro-CT and analyzed by histology, immunohistochemistry, and in situ hybridization. Plasma concentration of versican in PAH patients and controls was measured using ELISA. GAGα- and GAGβ-containing isoforms were identified in pulmonary arteriopathy of all patients. However, immunohistochemical staining of N-terminal G1 domain (versican G1) and C-terminal G3 domain (versican G3) using specific antibodies did not consistently co-localize. Tenascin-C was occasionally found in neointima, but also in thin-walled collateral vessels. Hyaluronan accumulated in the neointima, co-localizing with both versican G3 and the neoepitope DPEAAE. DPEAAE did not co-localize with the corresponding neoepitope of the C-terminal fragment generated by cleavage, possibly indicating motility of fragments. Patient plasma had a higher concentration of versican G3-containing fragments, compared to controls. The distribution of versican isoforms, cleavage products, and binding partners demonstrated here warrants further investigation of their functional roles in PAH, versican G3 was reinforced as a potential biomarker for PAH.

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Contribution to journal
publication status
epub
subject
in
The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society
article number
221554251331271
publisher
Histochemical Society Inc.
external identifiers
  • pmid:40219589
ISSN
0022-1554
DOI
10.1369/00221554251331271
language
English
LU publication?
yes
id
49b97f8e-243a-4b72-aa01-d6faa73f94e5
date added to LUP
2025-04-15 09:35:39
date last changed
2025-04-15 11:21:32
@article{49b97f8e-243a-4b72-aa01-d6faa73f94e5,
  abstract     = {{<p>Pulmonary arterial hypertension (PAH) is a lethal condition where expansion of the vascular extracellular matrix contributes to increased pulmonary vascular resistance. Versican, a chondroitin sulfate proteoglycan, is known to accumulate in vascular lesions of PAH and hyaluronan and tenascin-C, binding partners of versican, are elevated in PAH. The specific distribution and localization of versican isoforms, their cleavage products, and binding partners in vascular lesions of PAH had not been studied previously. Versican has five distinct isoforms, V0-V4, identified by the arrangement of its chondroitin-sulfate attachment regions, GAGα and GAGβ. Here, tissue from idiopathic PAH was imaged with synchrotron-based phase-contrast micro-CT and analyzed by histology, immunohistochemistry, and in situ hybridization. Plasma concentration of versican in PAH patients and controls was measured using ELISA. GAGα- and GAGβ-containing isoforms were identified in pulmonary arteriopathy of all patients. However, immunohistochemical staining of N-terminal G1 domain (versican G1) and C-terminal G3 domain (versican G3) using specific antibodies did not consistently co-localize. Tenascin-C was occasionally found in neointima, but also in thin-walled collateral vessels. Hyaluronan accumulated in the neointima, co-localizing with both versican G3 and the neoepitope DPEAAE. DPEAAE did not co-localize with the corresponding neoepitope of the C-terminal fragment generated by cleavage, possibly indicating motility of fragments. Patient plasma had a higher concentration of versican G3-containing fragments, compared to controls. The distribution of versican isoforms, cleavage products, and binding partners demonstrated here warrants further investigation of their functional roles in PAH, versican G3 was reinforced as a potential biomarker for PAH.</p>}},
  author       = {{Westöö, Christian and Mutgan, Ayse Ceren and van der Have, Oscar and Mead, Timothy J and Ahmed, Salaheldin and Lampei, Elna and Koch, Christopher D and Norvik, Christian and Aspberg, Anders and Bech, Martin and Peruzzi, Niccolò and Brunnström, Hans and Kwapiszewska, Grazyna and Rådegran, Göran and Apte, Suneel S and Tran-Lundmark, Karin}},
  issn         = {{0022-1554}},
  language     = {{eng}},
  month        = {{04}},
  publisher    = {{Histochemical Society Inc.}},
  series       = {{The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society}},
  title        = {{Localization, Proteolytic Processing, and Binding Partners of Versican Isoforms in Vascular Lesions of Pulmonary Arterial Hypertension}},
  url          = {{http://dx.doi.org/10.1369/00221554251331271}},
  doi          = {{10.1369/00221554251331271}},
  year         = {{2025}},
}