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We hypothesize that depleting EETs, via transgenic endothelial sEH overexpression, ablates protection of female brain against acute ischemic stroke. Nine-month-old female and male mice overexpressing human sEH in endothelium (Tie2hsEH) and WT littermates, with or without DM2, were subjected to 60-min middle cerebral artery occlusion. Plasma 14,15-EET concentration, brain capillary erythrocyte flux and infarct size at 24 h were measured. Tie2hsEH decreased 14,15-EET by 65% and 73%, capillary flux by 44% and 39%, and enlarged infarct size by 27% and 35% in DM2 and nondiabetic females, respectively. Tie2hsEH reduced male 14,15-EET by 39% only in nondiabetics, decreased capillary flux by 38% and 31% in DM2 and nondiabetics, respectively, without altering infarct size. DM2 did not alter 14,15-EET for either sex and had no effect on female capillary flux or infarct size. DM2 reduced capillary flux by 38% and 30%, and expanded infarct size by 33% and 32% in male Tie2hsEM and WT mice, respectively. EETs depletion by sEH overexpression overcomes intrinsic protection against acute microvascular and ischemic tissue injury in DM2 and nondiabetic adult\/middle-aged females.<\/jats:p>","DOI":"10.1177\/0271678x261471264","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T12:02:55Z","timestamp":1784116975000},"page":"3166-3178","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Endothelial expression of human soluble epoxide hydrolase worsens acute microvascular and tissue injury after stroke in female mice with early-stage diabetes mellitus"],"prefix":"10.1177","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5027-944X","authenticated-orcid":false,"given":"Wenbin","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Anesthesiology &amp; Perioperative Medicine, Oregon Health &amp; Science University, Portland, OR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E","family":"Shangraw","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology &amp; Perioperative Medicine, Oregon Health &amp; Science University, Portland, OR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9654-3509","authenticated-orcid":false,"given":"Catherine M","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology &amp; Perioperative Medicine, Oregon Health &amp; Science University, Portland, OR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elyse M","family":"Allen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology &amp; Perioperative Medicine, Oregon Health &amp; Science University, Portland, OR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah L","family":"Feller","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology &amp; Perioperative Medicine, Oregon Health &amp; Science University, Portland, OR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierno M","family":"Bah","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology &amp; Perioperative Medicine, Oregon Health &amp; Science University, Portland, OR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Libal","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology &amp; Perioperative Medicine, Oregon Health &amp; Science University, Portland, OR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Destine","family":"Krenik","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology &amp; Perioperative Medicine, Oregon Health &amp; Science University, Portland, OR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Ah","family":"Kim","sequence":"additional","affiliation":[{"name":"OHSU Integrated Genomics Laboratory, Oregon Health &amp; Science University, Portland, OR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruikang K","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3489-4730","authenticated-orcid":false,"given":"Nabil J","family":"Alkayed","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology &amp; Perioperative Medicine, Oregon Health &amp; Science University, Portland, OR, USA"},{"name":"Knight Cardiovascular Institute, Oregon Health &amp; Science University, Portland, OR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,8,2]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.prostaglandins.2018.07.002"},{"key":"e_1_3_3_3_2","article-title":"14,15-EET reduced brain injury from cerebral ischemia and reperfusion via suppressing neuronal parthanatos","volume":"22","author":"Zhao H","year":"2021","unstructured":"Zhao H, Tang J, Chen H, et al. 14,15-EET reduced brain injury from cerebral ischemia and reperfusion via suppressing neuronal parthanatos. 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