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We aimed to investigate the role of the endothelial extracellular matrix (ECM), specifically the pulmonary arterial basement membrane (BM), in influencing SMC proliferation and phenotypic changes in PH-LHD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>SMC hyperplasia and endothelial ECM remodelling were characterized histologically on human pulmonary arterial samples, and by mass spectrometry, and atomic force microscopy on decellularized ECM (dECM) produced in vitro by endothelial cells isolated from pulmonary arteries (PA) of LHD patients without pulmonary hypertension (LHD w\/o PH), PH-LHD patients, or healthy-heart controls. Proliferation and migration rates of SMC cultured on endothelial dECM were assessed by Ki67 immunostaining and by wound-healing assay, respectively. The role of mechanosensitive YAP1 in SMC hyperplasia was addressed in human cells and in an aortic-banding rat model of PH-LHD by analysing YAP1 activation and the effect of YAP1 inhibition. PA of LHD w\/o PH and PH-LHD patients showed extensive remodelling of the BM. This was confirmed in vitro as altered composition and stiffening of dECM generated by respective patient endothelial cells. ECM remodelling was associated with SMC accumulation in the pulmonary arterial intima in patient samples and promoted SMC migration and proliferation in vitro. Conversely, dECM generated by healthy human endothelial cells reduced the hypermigration and hyperproliferation of SMC from LHD w\/o PH and PH-LHD patients. Remodelling of the endothelial ECM in LHD w\/o PH and PH-LHD patients also activated YAP1 in SMC, inhibition of which reduced SMC migration and proliferation in vitro. These findings were reproduced in vivo in a rat model of PH-LHD induced by aortic-banding.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Here, we report endothelial ECM remodelling as a key mechanism driving SMC hyperplasia in PH-LHD. Notably, endothelial ECM remodelling is evident in both patients with LHD w\/o PH and those with PH-LHD, raising the possibility that it may reflect an early event in LHD-induced pulmonary vascular remodelling. This ECM remodelling is associated with YAP1 in adjacent SMC, promoting their migration and proliferation and contributing to SMC hyperplasia. Consequently, targeting ECM remodelling and YAP1 activation may offer promising therapeutic strategies for preventing of PA remodelling in PH-LHD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf238","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T12:28:15Z","timestamp":1763382495000},"page":"2939-2953","source":"Crossref","is-referenced-by-count":4,"title":["Remodelling of the endothelial extracellular matrix promotes smooth muscle cell hyperplasia in pulmonary hypertension due to left heart disease"],"prefix":"10.1093","volume":"121","author":[{"given":"Netra","family":"Nambiar Veetil","sequence":"first","affiliation":[{"name":"Institute of Physiology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , Charit\u00e9platz 1, Berlin 10117 ,","place":["Germany"]},{"name":"Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charit\u00e9 , Augustenburger Platz 1, Berlin 13353 ,","place":["Germany"]},{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , Charit\u00e9platz 1, Berlin 10117 ,","place":["Germany"]},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Berlin , Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tara","family":"Gransar","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , Charit\u00e9platz 1, Berlin 10117 ,","place":["Germany"]},{"name":"Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charit\u00e9 , Augustenburger Platz 1, Berlin 13353 ,","place":["Germany"]},{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , Charit\u00e9platz 1, Berlin 10117 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shao-Fei","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , Charit\u00e9platz 1, Berlin 10117 ,","place":["Germany"]},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Berlin , Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahed","family":"Almalla","sequence":"additional","affiliation":[{"name":"Institute of Chemistry and Biochemistry, Freie Universit\u00e4t Berlin , Takustr. 3, Berlin 14195 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieluise","family":"Kirchner","sequence":"additional","affiliation":[{"name":"Core Unit Proteomics, Berlin Institute of Health at Charit\u00e9-Universit\u00e4tsmedizin Berlin and Max-Delbr\u00fcck-Center for Molecular Medicine , Berlin 13125 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn","family":"Brackin-Helmers","sequence":"additional","affiliation":[{"name":"Advanced Medical Bioimaging Core Facility, Charit\u00e9-Universit\u00e4tsmedizin Berlin , Charit\u00e9platz 1, Berlin 10117 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Hennig","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charit\u00e9 , Augustenburger Platz 1, Berlin 13353 ,","place":["Germany"]},{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , Charit\u00e9platz 1, Berlin 10117 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruhi","family":"Yeter","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charit\u00e9 , Augustenburger Platz 1, Berlin 13353 ,","place":["Germany"]},{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , Charit\u00e9platz 1, Berlin 10117 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Weinhart","sequence":"additional","affiliation":[{"name":"Institute of Chemistry and Biochemistry, Freie Universit\u00e4t Berlin , Takustr. 3, Berlin 14195 ,","place":["Germany"]},{"name":"Institute of Physical Chemistry and Electrochemistry, Leibniz Universit\u00e4t 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for Cardiovascular Research), Partner Site Berlin , Berlin ,","place":["Germany"]},{"name":"Department of Health Science and Technology, Translational Cardiovascular Technology , LFW C 13.2, ETH Zurich, Universit\u00e4tstrasse 2, Z\u00fcrich 8092 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0450-7338","authenticated-orcid":false,"given":"Robert","family":"Szulcek","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , Charit\u00e9platz 1, Berlin 10117 ,","place":["Germany"]},{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , Charit\u00e9platz 1, Berlin 10117 ,","place":["Germany"]},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Berlin , Berlin ,","place":["Germany"]},{"name":"Department of Cardiac Anesthesiology and Intensive Care Medicine, Deutsches Herzzentrum der Charit\u00e9 , Augustenburger Platz 1, Berlin 13353 ,","place":["Germany"]},{"name":"DZL (German Centre for Lung Research), Partner Site Berlin , Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8637-2037","authenticated-orcid":false,"given":"Mariya M","family":"Kucherenko","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , Charit\u00e9platz 1, Berlin 10117 ,","place":["Germany"]},{"name":"Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charit\u00e9 , Augustenburger Platz 1, Berlin 13353 ,","place":["Germany"]},{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , Charit\u00e9platz 1, Berlin 10117 ,","place":["Germany"]},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Berlin , Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4100-2961","authenticated-orcid":false,"given":"Wolfgang M","family":"Kuebler","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , Charit\u00e9platz 1, Berlin 10117 ,","place":["Germany"]},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Berlin , Berlin ,","place":["Germany"]},{"name":"DZL (German Centre for Lung Research), Partner Site Berlin , Berlin ,","place":["Germany"]},{"name":"Departments of Physiology, University of Toronto , 1 King\u2019s College Circle, Toronto, ON M5S 1A8 ,","place":["Canada"]},{"name":"Department of Surgery, University of Toronto , 1 King\u2019s College Circle, Toronto, ON M5S 1A8 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8127-5019","authenticated-orcid":false,"given":"Christoph","family":"Knosalla","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charit\u00e9 , Augustenburger Platz 1, Berlin 13353 ,","place":["Germany"]},{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , Charit\u00e9platz 1, Berlin 10117 ,","place":["Germany"]},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Berlin , Berlin 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