{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T21:22:53Z","timestamp":1791840173432,"version":"4.3.4"},"reference-count":78,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","license":[{"start":{"date-parts":[[2024,5,24]],"date-time":"2024-05-24T00:00:00Z","timestamp":1716508800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2024,5,24]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Preclinical studies have shown the therapeutic potential of VEGF-B (vascular endothelial growth factor B) in revascularization of the ischemic myocardium, but the associated cardiac hypertrophy and adverse side effects remain a concern. To understand the importance of endothelial proliferation and migration for the beneficial versus adverse effects of VEGF-B in the heart, we explored the cardiac effects of autocrine versus paracrine VEGF-B expression in transgenic and gene-transduced mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We used single-cell RNA sequencing to compare cardiac endothelial gene expression in VEGF-B transgenic mouse models. Lineage tracing was used to identify the origin of a VEGF-B-induced novel endothelial cell population and adeno-associated virus\u2013mediated gene delivery to compare the effects of VEGF-B isoforms. Cardiac function was investigated using echocardiography, magnetic resonance imaging, and micro-computed tomography.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>Unlike in physiological cardiac hypertrophy driven by a cardiomyocyte-specific VEGF-B transgene (myosin heavy chain alpha-VEGF-B), autocrine VEGF-B expression in cardiac endothelium (aP2 [adipocyte protein 2]-VEGF-B) was associated with septal defects and failure to increase perfused subendocardial capillaries postnatally. Paracrine VEGF-B led to robust proliferation and myocardial migration of a novel cardiac endothelial cell lineage (VEGF-B-induced endothelial cells) of endocardial origin, whereas autocrine VEGF-B increased proliferation of VEGF-B-induced endothelial cells but failed to promote their migration and efficient contribution to myocardial capillaries. The surviving aP2-VEGF-B offspring showed an altered ratio of secreted VEGF-B isoforms and developed massive pathological cardiac hypertrophy with a distinct cardiac vessel pattern. In the normal heart, we found a small VEGF-B-induced endothelial cell population that was only minimally expanded during myocardial infarction but not during physiological cardiac hypertrophy associated with mouse pregnancy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Paracrine and autocrine secretions of VEGF-B induce expansion of a specific endocardium-derived endothelial cell population with distinct angiogenic markers. However, autocrine VEGF-B signaling fails to promote VEGF-B-induced endothelial cell migration and contribution to myocardial capillaries, predisposing to septal defects and inducing a mismatch between angiogenesis and myocardial growth, which results in pathological cardiac hypertrophy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.123.324136","type":"journal-article","created":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T05:00:27Z","timestamp":1713934827000},"page":"1465-1482","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["Contribution of VEGF-B-Induced Endocardial Endothelial Cell Lineage in Physiological Versus Pathological Cardiac Hypertrophy"],"prefix":"10.1161","volume":"134","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9377-8003","authenticated-orcid":true,"given":"Ibrahim","family":"Sultan","sequence":"first","affiliation":[{"name":"Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland."},{"name":"Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4048-4591","authenticated-orcid":true,"given":"Markus","family":"Ramste","sequence":"additional","affiliation":[{"name":"Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland."},{"name":"Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4891-1279","authenticated-orcid":true,"given":"Pim","family":"Peletier","sequence":"additional","affiliation":[{"name":"Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland."},{"name":"Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6151-1005","authenticated-orcid":true,"given":"Karthik Amudhala","family":"Hemanthakumar","sequence":"additional","affiliation":[{"name":"Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland."},{"name":"Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4854-6355","authenticated-orcid":true,"given":"Deepak","family":"Ramanujam","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, Technical University of Munich, DZHK partner site Munich Heart Alliance, Germany (D.R., S.E.)."},{"name":"RNATICS GmbH, Planegg, Germany (D.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annakaisa","family":"Tirronen","sequence":"additional","affiliation":[{"name":"A.I. 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