title: Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients.
abstract: Alterations in extracellular matrix (ECM) have been implicated in the pathophysiology of pulmonary hypertension. Here, we have undertaken a compartment-specific study to elucidate the expression profile of collagens and their processing enzymes in donor and idiopathic pulmonary arterial hypertension (IPAH) pulmonary arteries. Predominant intimal, but also medial and perivascular, remodeling and reduced lumen diameter were detected in IPAH pulmonary arteries. Two-photon microscopy demonstrated accumulation of collagen fibers. Quantification of collagen in pulmonary arteries revealed collagen accumulation mainly in the intima of IPAH pulmonary arteries compared with donors. Laser capture-microdissected pulmonary artery profiles (intima+media and perivascular tissue) were analyzed by real-time PCR for ECM gene expression. In the intima+media of IPAH vessels, collagens (COL4A5, COL14A1, and COL18A1), matrix metalloproteinase (MMP) 19, and a disintegrin and metalloprotease (ADAM) 33 were higher expressed, whereas MMP10, ADAM17, TIMP1, and TIMP3 were less abundant. Localization of COLXVIII, its cleavage product endostatin, and MMP10, ADAM33, and TIMP1 was confirmed in pulmonary arteries by immunohistochemistry. ELISA for collagen XVIII/endostatin demonstrated significantly elevated plasma levels in IPAH patients compared with donors, whereas circulating MMP10, ADAM33, and TIMP1 levels were similar between the two groups. Endostatin levels were correlated with pulmonary arterial wedge pressure, and established prognostic markers of IPAH, right atrial pressure, cardiac index, 6-min walking distance, NH2-terminal pro-brain natriuretic peptide, and uric acid. Expression of unstudied collagens, MMPs, ADAMs, and TIMPs were found to be significantly altered in IPAH intima+media. Elevated levels of circulating collagen XVIII/endostatin are associated with markers of a poor prognosis.
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria;
authors.forename: Julia
authors.initials: J
authors.lastname: Hoffmann
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria;
authors.forename: Leigh M
authors.initials: LM
authors.lastname: Marsh
authors.affiliation: Institute of Anatomy, University Lübeck, Lübeck, Germany and Airway Research Center North, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany;
authors.forename: Mario
authors.initials: M
authors.lastname: Pieper
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; Institute of Pathology, Medical University of Graz, Graz, Austria;
authors.forename: Elvira
authors.initials: E
authors.lastname: Stacher
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria;
authors.forename: Bahil
authors.initials: B
authors.lastname: Ghanim
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; Department of Pulmonology, Medical University of Graz, Graz, Austria;
authors.forename: Gabor
authors.initials: G
authors.lastname: Kovacs
authors.affiliation: Institute of Anatomy, University Lübeck, Lübeck, Germany and Airway Research Center North, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: König
authors.affiliation: Department of Pulmonology, Faculty of Medicine, Saarland University, Homburg/Saar, Germany;
authors.forename: Heinrike
authors.initials: H
authors.lastname: Wilkens
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University Southampton, UK; NIHR Southampton Respiratory BioMedical Research Unit at University Hospital Southampton, NHS Foundation Trust, UK; and.
authors.forename: Hans Michael
authors.initials: HM
authors.lastname: Haitchi
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria;
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria;
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.affiliation: Department of Pulmonology, Medical University of Graz, Graz, Austria;
authors.forename: Horst
authors.initials: H
authors.lastname: Olschewski
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; Department of Experimental Anesthesiology, Medical University of Graz, Graz, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Olschewski
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; Department of Experimental Anesthesiology, Medical University of Graz, Graz, Austria grazyna.kwapiszewska@lvr.lbg.ac.at.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Kwapiszewska
mesh_terms: D015415:Biomarkers / Q000097:blood; D003094:Collagen / Q000096:biosynthesis*; D043169:Endostatins / Q000097:blood; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D045726:Metalloproteases; D008875:Middle Aged; D011379:Prognosis; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology
chemical_list: D015415:Biomarkers; D043169:Endostatins; D003094:Collagen; D045726:Metalloproteases
keywords: collagen XVIII; endostatin; laser microdissection; vascular fibrosis; vascular remodeling
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