{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T02:16:56Z","timestamp":1789611416403,"version":"build-2803163510"},"reference-count":18,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2017,10,31]],"date-time":"2017-10-31T00:00:00Z","timestamp":1509408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["EU 121\/2-3"],"award-info":[{"award-number":["EU 121\/2-3"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Thyssen Stiftung","award":["Az. 10.11.2.142."],"award-info":[{"award-number":["Az. 10.11.2.142."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cardiac remodeling plays a crucial role in the development of heart failure after mycocardial infarction. Besides cardiomyocytes, endothelial cells are recognized to contribute to cardiac remodeling. We now investigated processes of endothelial mesenchymal transition (EndoMT) in microvascular endothelial cells of rat (MVEC) under hypoxia and paracrine effects on ventricular cardiomyocytes of adult rat. Exposure of MVECs to hypoxia\/reoxygenation enhanced TGF\u03b2\/SMAD signaling, since phosphorylation, and thus activation, of SMAD1\/5 and SMAD2 increased. This increase was blocked by inhibitors of TGF\u03b2 receptor types ALK1 or ALK5. Exposure of ventricular cardiomyocytes to conditioned medium from hypoxic\/reoxygenated MVECs enhanced SMAD2 phosphorylation and provoked apoptosis in cardiomyoyctes. Both were blocked by ALK5 inhibition. To analyze autocrine effects of hypoxic TGF\u03b2 signaling we investigated EndoMT in MVECs. After 3 days of hypoxia the mesenchymal marker protein \u03b1-smooth muscle actin (\u03b1-SMA), and the number of \u03b1-SMA- and fibroblast specific protein 1 (FSP1)-positive cells increased in MVECs cultures. This was blocked by ALK5 inhibition. Similarly, TGF\u03b21 provoked enhanced expression of \u03b1-SMA and FSP1 in MVECs. In conclusion, hypoxia provokes EndoMT in MVECs via TGF\u03b21\/SMAD2 signaling. Furthermore, release of TGF\u03b21 from MVECs acts in a paracrine loop on cardiomyocytes and provokes apoptotic death. Thus, in myocardial infarction hypoxic endothelial cells may contribute to cardiac remodeling and heart failure progression by promotion of cardiac fibrosis and cardiomyocytes death.<\/jats:p>","DOI":"10.3390\/ijms18112290","type":"journal-article","created":{"date-parts":[[2017,10,31]],"date-time":"2017-10-31T12:48:31Z","timestamp":1509454111000},"page":"2290","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Endothelial Mesenchymal Transition in Hypoxic Microvascular Endothelial Cells and Paracrine Induction of Cardiomyocyte Apoptosis Are Mediated via TGF\u03b21\/SMAD Signaling"],"prefix":"10.3390","volume":"18","author":[{"given":"Isabella","family":"Sniegon","sequence":"first","affiliation":[{"name":"Institute of Physiology, Justus Liebig University, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona","family":"Prie\u00df","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Justus Liebig University, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Heger","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Justus Liebig University, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer","family":"Schulz","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Justus Liebig University, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhild","family":"Euler","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Justus Liebig University, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1038\/nm1613","article-title":"Endothelial-to-mesenchymal transition contributes to cardiac fibrosis","volume":"13","author":"Zeisberg","year":"2007","journal-title":"Nat. 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