{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T15:34:16Z","timestamp":1792596856058,"version":"4.5.0"},"reference-count":52,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T00:00:00Z","timestamp":1664236800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT175257"],"award-info":[{"award-number":["PJT175257"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Angiogenesis inhibitor drugs targeting vascular endothelial growth factor (VEGF) signaling to the endothelial cell (EC) are used to treat various cancer types. However, primary or secondary resistance to therapy is common. Clinical and pre\u2010clinical studies suggest that alternative pro\u2010angiogenic factors are upregulated after VEGF pathway inhibition. Therefore, identification of alternative pro\u2010angiogenic pathway(s) is critical for the development of more effective anti\u2010angiogenic therapy. Here we study the role of apelin as a pro\u2010angiogenic G\u2010protein\u2010coupled receptor ligand in tumor growth and angiogenesis. We found that loss of apelin in mice delayed the primary tumor growth of Lewis lung carcinoma 1 and B16F10 melanoma when combined with the VEGF receptor tyrosine kinase inhibitor, sunitinib. Targeting apelin in combination with sunitinib markedly reduced the tumor vessel density, and decreased microvessel remodeling. Apelin loss reduced angiogenic sprouting and tip cell marker gene expression in comparison to the sunitinib\u2010alone\u2010treated mice. Single\u2010cell RNA sequencing of tumor EC demonstrated that the loss of apelin prevented EC tip cell differentiation. Thus, apelin is a potent pro\u2010angiogenic cue that supports initiation of tumor neovascularization. Together, our data suggest that targeting apelin may be useful as adjuvant therapy in combination with VEGF signaling inhibition to inhibit the growth of advanced tumors.<\/jats:p>","DOI":"10.1096\/fj.202200616rr","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T06:23:22Z","timestamp":1664259802000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Loss of apelin blocks the emergence of sprouting angiogenesis in experimental tumors"],"prefix":"10.1096","volume":"36","author":[{"given":"Abul K.","family":"Azad","sequence":"first","affiliation":[{"name":"Department of Medicine University of Alberta  Edmonton Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kieran R.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Lunenfeld\u2010Tanenbaum Research Institute University of Toronto  Toronto Ontario Canada"},{"name":"Department of 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