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

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Title: Localization, Proteolytic Processing, and Binding Partners of Versican Isoforms in Vascular Lesions of Pulmonary Arterial Hypertension
Authors: Westöö, Christian, Mutgan, Ayse Ceren, van der Have, Oscar, Mead, Timothy J, Ahmed, Salaheldin, Lampei, Elna, Koch, Christopher D, Norvik, Christian, Aspberg, Anders, Bech, Martin, Peruzzi, Niccolò, Brunnström, Hans, Kwapiszewska, Grazyna, Rådegran, Göran, Apte, Suneel S, Tran-Lundmark, Karin
Contributors: Lund University, Faculty of Medicine, Department of Experimental Medical Science, Vessel Wall Biology, Lunds universitet, Medicinska fakulteten, Institutionen för experimentell medicinsk vetenskap, Kärlväggsbiologi, Originator, Lund University, Faculty of Medicine, WCMM-Wallenberg Centre for Molecular Medicine, Lunds universitet, Medicinska fakulteten, WCMM- Wallenberg center för molekylär medicinsk forskning, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section II, Cardiology, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion II, Kardiologi, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section III, Rheumatology, Molecular Skeletal Biology, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion III, Reumatologi och molekylär skelettbiologi, Molekylär skelettbiologi, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section III, Rheumatology, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion III, Reumatologi och molekylär skelettbiologi, Originator, Lund University, Faculty of Engineering, LTH, LTH Profile areas, LTH Profile Area: Engineering Health, Lunds universitet, Lunds Tekniska Högskola, LTH profilområden, LTH profilområde: Teknik för hälsa, Originator, Lund University, Faculty of Science, Medical Radiation Physics, Lund, X-ray Phase Contrast, Lunds universitet, Naturvetenskapliga fakulteten, Medicinsk strålningsfysik, Lund, X-ray Phase Contrast, Originator, Lund University, Faculty of Science, Medical Radiation Physics, Lund, Lunds universitet, Naturvetenskapliga fakulteten, Medicinsk strålningsfysik, Lund, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section V, Pathology, Lund, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion V, Patologi, Lund, Originator, Lund University, Profile areas and other strong research environments, Other Strong Research Environments, LUCC: Lund University Cancer Centre, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Övriga starka forskningsmiljöer, LUCC: Lunds universitets cancercentrum, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section V, Pathology, Lund, Improved diagnostics and prognostics of lung cancer and metastases to the lungs, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion V, Patologi, Lund, Förbättrad diagnostik och prognostik vid lungcancer och metastaser till lunga, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section II, Cardiology, Lund Hemodynamic Lab, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion II, Kardiologi, Lund Hemodynamic Lab, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section II, Thoracic Surgery, Cardiopulmonary disease - information, support and reception, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion II, Thoraxkirurgi, Hjärt-lungsjukdom - information, stöd och bemötande, Originator
Source: The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society Lecticans in Vascular Remodeling of the Pulmonary and Fetal Circulation. 73(3-4):129-145
Subject Terms: Medical and Health Sciences, Clinical Medicine, Respiratory Medicine and Allergy, Medicin och hälsovetenskap, Klinisk medicin, Lungmedicin och allergi, Cardiology and Cardiovascular Disease, Kardiologi och kardiovaskulära sjukdomar
Description: 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.
Access URL: https://doi.org/10.1369/00221554251331271
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  Data: Localization, Proteolytic Processing, and Binding Partners of Versican Isoforms in Vascular Lesions of Pulmonary Arterial Hypertension
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  Data: Lund University, Faculty of Medicine, Department of Experimental Medical Science, Vessel Wall Biology, Lunds universitet, Medicinska fakulteten, Institutionen för experimentell medicinsk vetenskap, Kärlväggsbiologi, Originator<br />Lund University, Faculty of Medicine, WCMM-Wallenberg Centre for Molecular Medicine, Lunds universitet, Medicinska fakulteten, WCMM- Wallenberg center för molekylär medicinsk forskning, Originator<br />Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section II, Cardiology, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion II, Kardiologi, Originator<br />Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section III, Rheumatology, Molecular Skeletal Biology, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion III, Reumatologi och molekylär skelettbiologi, Molekylär skelettbiologi, Originator<br />Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section III, Rheumatology, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion III, Reumatologi och molekylär skelettbiologi, Originator<br />Lund University, Faculty of Engineering, LTH, LTH Profile areas, LTH Profile Area: Engineering Health, Lunds universitet, Lunds Tekniska Högskola, LTH profilområden, LTH profilområde: Teknik för hälsa, Originator<br />Lund University, Faculty of Science, Medical Radiation Physics, Lund, X-ray Phase Contrast, Lunds universitet, Naturvetenskapliga fakulteten, Medicinsk strålningsfysik, Lund, X-ray Phase Contrast, Originator<br />Lund University, Faculty of Science, Medical Radiation Physics, Lund, Lunds universitet, Naturvetenskapliga fakulteten, Medicinsk strålningsfysik, Lund, Originator<br />Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section V, Pathology, Lund, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion V, Patologi, Lund, Originator<br />Lund University, Profile areas and other strong research environments, Other Strong Research Environments, LUCC: Lund University Cancer Centre, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Övriga starka forskningsmiljöer, LUCC: Lunds universitets cancercentrum, Originator<br />Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section V, Pathology, Lund, Improved diagnostics and prognostics of lung cancer and metastases to the lungs, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion V, Patologi, Lund, Förbättrad diagnostik och prognostik vid lungcancer och metastaser till lunga, Originator<br />Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section II, Cardiology, Lund Hemodynamic Lab, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion II, Kardiologi, Lund Hemodynamic Lab, Originator<br />Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section II, Thoracic Surgery, Cardiopulmonary disease - information, support and reception, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion II, Thoraxkirurgi, Hjärt-lungsjukdom - information, stöd och bemötande, Originator
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  Data: 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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