{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T17:18:24Z","timestamp":1790183904153,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2018,3,9]],"date-time":"2018-03-09T00:00:00Z","timestamp":1520553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["P27848\u2010B28"],"award-info":[{"award-number":["P27848\u2010B28"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC1213"],"award-info":[{"award-number":["CRC1213"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pulmonary vascular remodeling is the main pathological hallmark of pulmonary hypertension disease. We undertook a comprehensive and multilevel approach to investigate the origin of smooth muscle actin\u2010expressing cells in remodeled vessels. Transgenic mice that allow for specific, inducible, and permanent labeling of endothelial (<jats:italic>Cdh5\u2010tdTomato<\/jats:italic>), smooth muscle (<jats:italic>Acta2\u2010, Myh11\u2010tdTomato<\/jats:italic>), pericyte (<jats:italic>Cspg4\u2010tdTomato<\/jats:italic>), and fibroblast (<jats:italic>Pdgfra\u2010tdTomato<\/jats:italic>) lineages were used to delineate the cellular origins of pulmonary vascular remodeling. Mapping the fate of major lung resident cell types revealed smooth muscle cells (SMCs) as the predominant source of cells that populate remodeled pulmonary vessels in chronic hypoxia and allergen\u2010induced murine models. Combining <jats:italic>in vivo<\/jats:italic> cell type\u2010specific, time\u2010controlled labeling of proliferating cells with a pulmonary artery phenotypic explant assay, we identified proliferation of SMCs as an underlying remodeling pathomechanism. Multicolor immunofluorescence analysis showed a preserved pattern of cell type marker localization in murine and human pulmonary arteries, in both donors and idiopathic pulmonary arterial hypertension (IPAH) patients. Whilst neural glial antigen 2 (chondroitin sulfate proteoglycan 4) labeled mostly vascular supportive cells with partial overlap with SMC markers, PDGFR\u03b1\u2010expressing cells were observed in the perivascular compartment. The luminal vessel side was lined by a single cell layer expressing endothelial markers followed by an adjacent and distinct layer defined by SMC marker expression and pronounced thickening in remodeled vessels. Quantitative flow cytometric analysis of single cell digests of diverse pulmonary artery layers showed the preserved separation into two discrete cell populations expressing either endothelial cell (EC) or SMC markers in human remodeled vessels. Additionally, we found no evidence of overlap between EC and SMC ultrastructural characteristics using electron microscopy in either donor or IPAH arteries. Lineage\u2010specific marker expression profiles are retained during pulmonary vascular remodeling without any indication of cell type conversion. The expansion of resident SMCs is the major underlying and evolutionarily conserved paradigm of pulmonary vascular disease pathogenesis. \u00a9 2018 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.5044","type":"journal-article","created":{"date-parts":[[2018,1,23]],"date-time":"2018-01-23T06:18:51Z","timestamp":1516688331000},"page":"485-498","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Resident cell lineages are preserved in pulmonary vascular remodeling"],"prefix":"10.1002","volume":"244","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0820-3318","authenticated-orcid":false,"given":"Slaven","family":"Crnkovic","sequence":"first","affiliation":[{"name":"Ludwig Boltzmann Institute for Lung Vascular Research  Graz Austria"},{"name":"Department of Physiology Medical University of Graz  Graz Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leigh M","family":"Marsh","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Lung Vascular Research  Graz Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elie","family":"El Agha","sequence":"additional","affiliation":[{"name":"Excellence Cluster Cardio\u2010Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center (UGMLC) Justus Liebig University Giessen  Giessen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Voswinckel","sequence":"additional","affiliation":[{"name":"Clinic for Internal Medicine Friedberg Hospital  Friedberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bahil","family":"Ghanim","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery Medical University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Klepetko","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery Medical University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvira","family":"Stacher\u2010Priehse","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Lung Vascular Research  Graz Austria"},{"name":"Institute of Pathology Medical University of Graz  Graz Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horst","family":"Olschewski","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Pulmonology Medical University of Graz  Graz Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilhelm","family":"Bloch","sequence":"additional","affiliation":[{"name":"German Sports University Cologne  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saverio","family":"Bellusci","sequence":"additional","affiliation":[{"name":"Excellence Cluster Cardio\u2010Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center (UGMLC) Justus Liebig University Giessen  Giessen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Olschewski","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Lung Vascular Research  Graz Austria"},{"name":"Department of Physiology Medical University of Graz  Graz Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazyna","family":"Kwapiszewska","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Lung Vascular Research  Graz Austria"},{"name":"Department of Physiology Medical University of Graz  Graz Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,3,9]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.911818"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201201-0164OC"},{"key":"e_1_2_8_4_1","first-page":"37","article-title":"Development of pulmonary arterial changes in rats fed Crotalaria spectabilis","volume":"94","author":"Meyrick B","year":"1979","journal-title":"Am J Pathol"},{"key":"e_1_2_8_5_1","first-page":"51","article-title":"Hypoxia and incorporation of 3H\u2010thymidine by cells of the rat pulmonary arteries and alveolar wall","volume":"96","author":"Meyrick B","year":"1979","journal-title":"Am J Pathol"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.3109\/01902148109052325"},{"key":"e_1_2_8_7_1","first-page":"84","article-title":"Crotalaria\u2010induced pulmonary hypertension. 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