Zhu_2026_J.Cereb.Blood.Flow.Metab__271678x261471264

Female mice are protected from diabetes mellitus type 2 (DM2)-exacerbation of ischemic brain injury, concurrently expressing less soluble epoxide hydrolase (sEH), which degrades neuroprotective epoxyeicosatrienoates (EETs). 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 24h 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.