Christian Westöö, Ayse Ceren Mutgan, Oscar van der Have, Timothy J. Mead, Salaheldin Ahmed, Elna Lampei, Christopher D. Koch, Christian Norvik, Anders Aspberg, Martin Bech, Niccolò Peruzzi, Hans Brunnström, Grazyna Kwapiszewska, Göran Rådegran, Suneel S. Apte, Karin Tran-Lundmark
Lund University. Medical University of Graz. Skåne University Hospital. Cleveland Clinic Lerner Research Institute. Case Western Reserve University. University Hospitals Rainbow Babies & Children’s Hospital. Helsingborg Hospital. Sanford School of Medicine and University of South Dakota. German Center for Lung Research
Sweden, Austria, United States and Germany
Journal of Histochemistry and Cytochemistry
J Histochem Cytochem 2025;
DOI: 10.1369/00221554251331271
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 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.
Category
Class I. Idiopathic Pulmonary Hypertension
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Pulmonary Vascular Pathology
Age Focus: Pediatric Pulmonary Vascular Disease or Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
ree PDF File or Full Text Article Available Through PubMed or DOI: Yes