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Current therapies for treating ocular angiogenesis are centered on the inhibition of vascular endothelial growth factor (VEGF). While clinically effective, some AMD patients are refractory or develop resistance to anti\u2010VEGF therapies and concerns of increased risks of developing geographic atrophy following long\u2010term treatment have been raised. Identification of alternative pathways to inhibit pathological angiogenesis is thus important. We have identified a novel inhibitor of angiogenesis, COCO, a member of the Cerberus\u2010related DAN protein family. We demonstrate that COCO inhibits sprouting, migration and cellular proliferation of cultured endothelial cells. Intravitreal injections of COCO inhibited retinal vascularization during development and in models of retinopathy of prematurity. COCO equally abrogated angiogenesis in models of choroidal neovascularization. Mechanistically, COCO inhibited TGF\u03b2 and BMP pathways and altered energy metabolism and redox balance of endothelial cells. Together, these data show that COCO is an inhibitor of retinal and choroidal angiogenesis, possibly representing a therapeutic option for the treatment of neovascular ocular diseases.<\/jats:p>","DOI":"10.15252\/emmm.202012005","type":"journal-article","created":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T02:10:27Z","timestamp":1613614227000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["COCO\/DAND5 inhibits developmental and pathological ocular angiogenesis"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8324-4099","authenticated-orcid":false,"given":"Natalija","family":"Popovic","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4515-4041","authenticated-orcid":false,"given":"Erika","family":"Hooker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Barabino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Flamier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2432-7580","authenticated-orcid":false,"given":"Fr\u00e9d\u00e9ric","family":"Provost","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Buscarlet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9649-6538","authenticated-orcid":false,"given":"Gilbert","family":"Bernier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1388-3108","authenticated-orcid":false,"given":"Bruno","family":"Larriv\u00e9e","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,2,15]]},"reference":[{"key":"BFEMMM202012005_CR1","doi-asserted-by":"crossref","first-page":"F1477","DOI":"10.1152\/ajprenal.00182.2013","volume":"305","author":"Y Abe","year":"2013","unstructured":"Abe Y, Sakairi T, Beeson C, Kopp JB (2013) TGF\u2010\u03b21 stimulates mitochondrial oxidative phosphorylation and generation of reactive oxygen species in cultured mouse podocytes, mediated in part by the mTOR pathway. 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