{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T14:02:41Z","timestamp":1785333761901,"version":"3.55.0"},"reference-count":85,"publisher":"The Company of Biologists","issue":"14","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["R01 HL173766"],"award-info":[{"award-number":["R01 HL173766"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006537","name":"Vanderbilt University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006537","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Abnormal cardiac trabeculation often leads to congenital heart disease (CHD). TIE2-ANG1 signaling is a key regulator of endocardial growth during trabeculation. However, little is known about the underlying mechanisms. Here, we demonstrate that loss of endocardial Tie2 via Nfatc1Cre resulted in increased nuclear localization of forkhead box O1 (FOXO1), reduced phosphorylation of AKT (the direct regulator of FOXO1) and reduced expression of several proliferation promoting genes in endocardial cells (EdCs). The cardiac defects seen in endocardial Tie2-deficient mouse hearts were phenocopied by forced activation of FOXO1 within the endocardium and partially rescued by loss of Foxo1. Conversely, excessive PI3K signaling (the direct regulator of phosphorylation of AKT) in EdCs caused cardiac hypotrabeculation. Further, we identify that endocardial loss of Tie2 resulted in impaired cleavage of versican, which was associated with enhanced expression of ADAMTS endogenous inhibitor TIMP3 in Tie2-cko EdCs. Thus, our results suggest that TIE2 signaling in the early embryonic endocardium promotes endocardial growth via sequestering FOXO1 within the cytoplasm and modulates cardiomyocyte proliferation via stimulating versican cleavage to orchestrate myocardial trabeculation, providing insights into the pathogenesis of CHD.<\/jats:p>","DOI":"10.1242\/dev.205674","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T09:09:52Z","timestamp":1782724192000},"source":"Crossref","is-referenced-by-count":1,"title":["Endocardial TIE2 orchestrates cardiac trabeculation via sequestering FOXO1 within the cytoplasm and stimulating versican cleavage"],"prefix":"10.1242","volume":"153","author":[{"given":"H. Scott","family":"Baldwin","sequence":"first","affiliation":[{"name":"Vanderbilt University Medical Center 1 Department of Pediatrics (Cardiology) , , Nashville, TN 37232 ,","place":["USA"]},{"name":"Vanderbilt University 2 Department of Cell and Development Biology , , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Tompkins","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center 1 Department of Pediatrics (Cardiology) , , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Gong","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center 1 Department of Pediatrics (Cardiology) , , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Helm","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center 3 Department of Biostatistics , , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Liu","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center 3 Department of Biostatistics , , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1701-812X","authenticated-orcid":false,"given":"Xianghu","family":"Qu","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center 1 Department of Pediatrics (Cardiology) , , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"2026072909113495600_DEV205674C1","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1161\/01.ATV.0000110502.10593.06","article-title":"Vascular endothelial growth factor activates PI3K\/Akt\/forkhead signaling in endothelial cells","volume":"24","author":"Abid","year":"2004","journal-title":"Arterioscler. 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