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In the present study, we chronically infused mice with ketorolac, a non\u2010specific COX inhibitor that does not cross the blood\u2013brain barrier (BBB), under normoxia or 50% isobaric hypoxia (10% O<jats:sub>2<\/jats:sub> by volume). Ketorolac increased mortality rate under hypoxia in a dose\u2010dependent manner. Using in vivo multiphoton microscopy, we demonstrated that chronic COX inhibition completely attenuated brain angiogenic response to hypoxia. Alterations in a number of angiogenic factors that were reported to be COX\u2010dependent in other models were assayed at 24\u2010hr and 10\u2010day hypoxia. Intriguingly, hypoxia\u2010inducible factor 1 was unaffected under COX inhibition, and vascular endothelial growth factor receptor type 2 (VEGFR2) and C\u2010X\u2010C chemokine receptor type 4 (CXCR4) were significantly but slightly decreased. However, a number of mitogen\u2010activated protein kinases (MAPKs) were significantly reduced upon COX inhibition. We conclude that additional, angiogenic factor\u2010independent mechanism might contribute to COX role in brain angioplasticity, probably including mitogenic COX effect on endothelium. Our data indicate that COX activity is critical for systemic adaptation to chronic hypoxia, and BBB COX is essential for hypoxia\u2010induced brain angioplasticity. These data also indicate a potential risk for using COX inhibitors under hypoxia conditions in clinics. Further studies are required to elucidate a complete mechanism for brain long\u2010term angiogenesis regulation through COX activity.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15291-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15291","type":"journal-article","created":{"date-parts":[[2021,1,3]],"date-time":"2021-01-03T02:36:20Z","timestamp":1609641380000},"page":"246-261","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Cyclooxygenase inhibition attenuates brain angiogenesis and independently decreases mouse survival under hypoxia"],"prefix":"10.1111","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9382-2753","authenticated-orcid":false,"given":"Drew R.","family":"Seeger","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences University of North Dakota Grand Forks ND USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svetlana A.","family":"Golovko","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of North Dakota Grand Forks ND USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bryon D.","family":"Grove","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of North Dakota Grand Forks ND USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1749-3158","authenticated-orcid":false,"given":"Mikhail Y.","family":"Golovko","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of North Dakota Grand Forks ND USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,2,25]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00086.2017"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1996.271.4.H1541"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3171\/jns.1996.85.6.1078"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1558"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2011.03.016"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2014.04.035"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2012.06.055"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03401992"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST20110643"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11745-013-3767-5"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11745-013-3767-5"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.plefa.2013.09.005"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11745-016-4144-y"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.D013441"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00052.2019"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12865-020-00347-y"},{"key":"e_1_2_10_18_1","first-page":"275","volume-title":"Novel Biochemical, Pharmacological and Clinical Aspects of Cytidinediphosphocholine","author":"Clendenon N. 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