| Autor: |
Mutgan AC; Division of Physiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria.; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria., Radic N; Division of Physiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria., Valzano F; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria., Crnkovic S; Division of Physiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria.; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; Institute for Lung Health, Cardiopulmonary Institute, Member of the German Lung Center (DZL), Giessen, Germany., El-Merhie N; Institute for Lung Health, Cardiopulmonary Institute, Member of the German Lung Center (DZL), Giessen, Germany., Evermann M; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria., Hoetzenecker K; Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria., Foris V; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria., Brcic L; Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria., Marsh LM; Division of Physiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria.; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria., Tran-Lundmark K; Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden.; Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden.; The Pediatric Heart Center, Skåne University Hospital, Lund, Sweden., Jandl K; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria., Kwapiszewska G; Division of Physiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria.; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; Institute for Lung Health, Cardiopulmonary Institute, Member of the German Lung Center (DZL), Giessen, Germany. |
| Abstrakt: |
Changes in the extracellular matrix of pulmonary arteries (PAs) are a key aspect of vascular remodeling in pulmonary hypertension (PH). Yet, our understanding of the alterations affecting the proteoglycan (PG) family remains limited. We sought to investigate the expression and spatial distribution of major vascular PGs in PAs from healthy individuals and various PH groups (chronic obstructive pulmonary disease: PH-COPD, pulmonary fibrosis: PH-PF, idiopathic: IPAH). PG regulation, deposition, and synthesis were notably heightened in IPAH, followed by PH-PF, with minor alterations in PH-COPD. Single-cell analysis unveiled cell-type and disease-specific PG regulation. Agrin expression, a basement membrane PG, was increased in IPAH, with PA endothelial cells (PAECs) identified as a major source. PA smooth muscle cells (PASMCs) mainly produced large-PGs, aggrecan and versican, and small-leucine-like proteoglycan (SLRP) biglycan, whereas the major PGs produced by adventitial fibroblasts were SLRP decorin and lumican. In IPAH and PF-PH, the neointima-forming PASMC population increased the expression of all investigated large-PGs and SLRPs, except fibroblast-predominant decorin (DCN). Expression of lumican, versican, and biglycan also positively correlated with collagen 1α1/1α2 expression in PASMCs in patients with IPAH and PH-PF. We demonstrated that transforming growth factor-beta (TGF-β) regulates versican and biglycan expression, indicating their contribution to vessel fibrosis in IPAH and PF-PH. We furthermore show that certain circulating PG levels display a disease-dependent pattern, with increased decorin and lumican across all patient groups, while versican was elevated in PH-COPD and IPAH and biglycan reduced in IPAH. These findings suggest unique compartment-specific PG regulation in different forms of PH, indicating distinct pathological processes. NEW & NOTEWORTHY Idiopathic pulmonary arterial hypertension (IPAH) pulmonary arteries (PAs) displayed the greatest proteoglycan (PG) changes, with PH associated with pulmonary fibrosis (PH-PF) and PH associated with chronic obstructive pulmonary disease (PH-COPD) following. Agrin, an endothelial cell-specific PG, was solely upregulated in IPAH. Among all cells, neo-intima-forming smooth muscle cells (SMCs) displayed the most significant PG increase. Increased levels of circulating decorin, lumican, and versican, mainly derived from SMCs, and adventitial fibroblasts, may serve as systemic indicators of pulmonary remodeling, reflecting perivascular fibrosis and neointima formation. |
