{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T20:03:31Z","timestamp":1789502611522,"version":"build-2803163510"},"reference-count":66,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,7,9]],"date-time":"2019-07-09T00:00:00Z","timestamp":1562630400000},"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":["SCHA 808\/7-1"],"award-info":[{"award-number":["SCHA 808\/7-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National and European Union funds","award":["MIS 379527"],"award-info":[{"award-number":["MIS 379527"]}]},{"name":"Margarethe Waitz Foundation","award":["research fellowship"],"award-info":[{"award-number":["research fellowship"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Experimental and human autopsy studies have associated adventitial lymphangiogenesis with atherosclerosis. An analysis of perivascular lymphangiogenesis in patients with coronary artery disease is lacking. Here, we examined lymphangiogenesis and its potential regulators in perivascular adipose tissue (PVAT) surrounding the heart (C-PVAT) and compared it with PVAT of the internal mammary artery (IMA-PVAT). Forty-six patients undergoing coronary artery bypass graft surgery were included. Perioperatively collected C-PVAT and IMA-PVAT were analyzed using histology, immunohistochemistry, real time PCR, and PVAT-conditioned medium using cytokine arrays. C-PVAT exhibited increased PECAM-1 (platelet endothelial cell adhesion molecule 1)-positive vessel density. The number of lymphatic vessels expressing lymphatic vessel endothelial hyaluronan receptor-1 or podoplanin was also elevated in C-PVAT and associated with higher inflammatory cell numbers, increased intercellular adhesion molecule 1 (ICAM1) expression, and fibrosis. Significantly higher expression of regulators of lymphangiogenesis such as vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor-3 was observed in C-PVAT compared to IMA-PVAT. Cytokine arrays identified angiopoietin-2 as more highly expressed in C-PVAT vs. IMA-PVAT. Findings were confirmed histologically and at the mRNA level. Stimulation of human lymphatic endothelial cells with recombinant angiopoietin-2 in combination with VEGF-C enhanced sprout formation. Our study shows that PVAT surrounding atherosclerotic arteries exhibits more extensive lymphangiogenesis, inflammation, and fibrosis compared to PVAT surrounding a non-diseased vessel, possibly due to local angiopoietin-2, VEGF-C, and VEGF-D overexpression.<\/jats:p>","DOI":"10.3390\/jcm8071000","type":"journal-article","created":{"date-parts":[[2019,7,10]],"date-time":"2019-07-10T03:05:26Z","timestamp":1562727926000},"page":"1000","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Increased Lymphangiogenesis and Lymphangiogenic Growth Factor Expression in Perivascular Adipose Tissue of Patients with Coronary Artery Disease"],"prefix":"10.3390","volume":"8","author":[{"given":"Ioannis","family":"Drosos","sequence":"first","affiliation":[{"name":"Center for Cardiology, Cardiology 1, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Pavlaki","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Democritus University of Thrace, 68100 Alexandroupolis, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Ortega Carrillo","sequence":"additional","affiliation":[{"name":"Center for Cardiology, Cardiology 1, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriani","family":"Kourkouli","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Democritus University of Thrace, 68100 Alexandroupolis, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Buschmann","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic and Vascular Surgery, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fotios","family":"Konstantinou","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Democritus University of Thrace, 68100 Alexandroupolis, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajinikanth","family":"Gogiraju","sequence":"additional","affiliation":[{"name":"Center for Cardiology, Cardiology 1, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Bochenek","sequence":"additional","affiliation":[{"name":"Center for Cardiology, Cardiology 1, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"},{"name":"Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Chalikias","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Democritus University of Thrace, 68100 Alexandroupolis, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos","family":"Tortopidis","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Democritus University of Thrace, 68100 Alexandroupolis, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Vahl","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic and Vascular Surgery, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Mikroulis","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Democritus University of Thrace, 68100 Alexandroupolis, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4982-9181","authenticated-orcid":false,"given":"Dimitrios","family":"Tziakas","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Democritus University of Thrace, 68100 Alexandroupolis, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5503-4150","authenticated-orcid":false,"given":"Thomas","family":"M\u00fcnzel","sequence":"additional","affiliation":[{"name":"Center for Cardiology, Cardiology 1, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stavros","family":"Konstantinides","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Democritus University of Thrace, 68100 Alexandroupolis, Greece"},{"name":"Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Sch\u00e4fer","sequence":"additional","affiliation":[{"name":"Center for Cardiology, Cardiology 1, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4736","DOI":"10.1073\/pnas.0730843100","article-title":"Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis","volume":"100","author":"Moulton","year":"2003","journal-title":"Proc. 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