{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T23:12:56Z","timestamp":1791241976001,"version":"4.1.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"22","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,5,28]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Heart failure, which is a major global health problem, is often preceded by pathological cardiac hypertrophy. The expansion of the cardiac vasculature, to maintain adequate supply of oxygen and nutrients, is a key determinant of whether the heart grows in a physiological compensated manner or a pathological decompensated manner. Bidirectional endothelial cell (EC)\u2013cardiomyocyte (CMC) cross talk via cardiokine and angiocrine signaling plays an essential role in the regulation of cardiac growth and homeostasis. Currently, the mechanisms involved in the EC-CMC interaction are not fully understood, and very little is known about the EC-derived signals involved. Understanding how an excess of angiogenesis induces cardiac hypertrophy and how ECs regulate CMC homeostasis could provide novel therapeutic targets for heart failure.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Genetic mouse models were used to delete vascular endothelial growth factor (VEGF) receptors, adeno-associated viral vectors to transduce the myocardium, and pharmacological inhibitors to block VEGF and ErbB signaling in vivo. Cell culture experiments were used for mechanistic studies, and quantitative polymerase chain reaction, microarrays, ELISA, and immunohistochemistry were used to analyze the cardiac phenotypes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>Both EC deletion of VEGF receptor (VEGFR)-1 and adeno-associated viral vector\u2013mediated delivery of the VEGFR1-specific ligands VEGF-B or placental growth factor into the myocardium increased the coronary vasculature and induced CMC hypertrophy in adult mice. The resulting cardiac hypertrophy was physiological, as indicated by preserved cardiac function and exercise capacity and lack of pathological gene activation. These changes were mediated by increased VEGF signaling via endothelial VEGFR2, because the effects of VEGF-B and placental growth factor on both angiogenesis and CMC growth were fully inhibited by treatment with antibodies blocking VEGFR2 or by endothelial deletion of VEGFR2. To identify activated pathways downstream of VEGFR2, whole-genome transcriptomics and secretome analyses were performed, and the Notch and ErbB pathways were shown to be involved in transducing signals for EC-CMC cross talk in response to angiogenesis. Pharmacological or genetic blocking of ErbB signaling also inhibited part of the VEGF-B\u2013induced effects in the heart.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>This study reveals that cross talk between the EC VEGFR2 and CMC ErbB signaling pathways coordinates CMC hypertrophy with angiogenesis, contributing to physiological cardiac growth.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.118.036099","type":"journal-article","created":{"date-parts":[[2019,3,29]],"date-time":"2019-03-29T09:01:07Z","timestamp":1553850067000},"page":"2570-2584","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":160,"title":["Endothelial Cells Regulate Physiological Cardiomyocyte Growth via VEGFR2-Mediated Paracrine Signaling"],"prefix":"10.1161","volume":"139","author":[{"given":"Riikka","family":"Kivel\u00e4","sequence":"first","affiliation":[{"name":"Wihuri Research Institute, Helsinki, Finland and Translational Cancer Biology Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Finland (R.K., K.A.H., M.R., K.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthik Amudhala","family":"Hemanthakumar","sequence":"additional","affiliation":[{"name":"Wihuri Research Institute, Helsinki, Finland and Translational Cancer Biology Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Finland (R.K., K.A.H., M.R., K.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katri","family":"Vaparanta","sequence":"additional","affiliation":[{"name":"MediCity Research Laboratories and Institute of Biomedicine, Faculty of Medicine, University of Turku, Finland (K.V., K.E.)."},{"name":"Turku Centre for Biotechnology, University of Turku and \u00c5bo Akademi University, Finland (K.V., K.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius","family":"Robciuc","sequence":"additional","affiliation":[{"name":"Wihuri Research Institute, Helsinki, Finland and Translational Cancer Biology Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Finland (R.K., K.A.H., M.R., K.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Izumiya","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Japan (Y.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyasu","family":"Kidoya","sequence":"additional","affiliation":[{"name":"Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Japan (H.K., N.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyuki","family":"Takakura","sequence":"additional","affiliation":[{"name":"Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Japan (H.K., N.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuyang","family":"Peng","sequence":"additional","affiliation":[{"name":"Maine Medical Center, Portland (X.P., D.B.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas B.","family":"Sawyer","sequence":"additional","affiliation":[{"name":"Maine Medical Center, Portland (X.P., D.B.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Elenius","sequence":"additional","affiliation":[{"name":"MediCity Research Laboratories and Institute of Biomedicine, Faculty of Medicine, University of Turku, Finland (K.V., K.E.)."},{"name":"Turku Centre for Biotechnology, University of Turku and \u00c5bo Akademi University, Finland (K.V., K.E.)."},{"name":"Department of Oncology and Radiotherapy, University of Turku and Turku University Hospital, Finland (K.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Walsh","sequence":"additional","affiliation":[{"name":"Robert M. 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