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Objective  Outcome after aneurysmal subarachnoid hemorrhage ( SAH ) depends critically on delayed cerebral ischemia ( DCI ) – a process driven primarily by vascular events including cerebral vasospasm, microvessel thrombosis, and microvascular dysfunction. This study sought to determine the impact of postconditioning – the phenomenon whereby endogenous protection against severe injury is enhanced by subsequent exposure to a mild stressor – on  SAH ‐induced  DCI .    Methods  Adult male C57BL/6 mice were subjected to sham,  SAH , or  SAH  plus isoflurane postconditioning. Neurological outcome was assessed daily via sensorimotor scoring. Contributors to  DCI  including cerebral vasospasm, microvessel thrombosis, and microvascular dysfunction were measured 3 days later. Isoflurane‐induced changes in hypoxia‐inducible factor 1alpha ( HIF ‐1 α )‐dependent genes were assessed via quantitative polymerase chain reaction.  HIF ‐1 α  was inhibited pharmacologically via 2‐methoxyestradiol (2 ME 2) or genetically via endothelial cell  HIF ‐1 α ‐null mice ( EC ‐ HIF ‐1 α ‐null). All experiments were performed in a randomized and blinded fashion.    Results  Isoflurane postconditioning initiated at clinically relevant time points after  SAH  significantly reduced cerebral vasospasm, microvessel thrombosis, microvascular dysfunction, and neurological deficits in wild‐type ( WT ) mice. Isoflurane modulated  HIF ‐1 α ‐dependent genes – changes that were abolished in 2 ME 2‐treated  WT  mice and  EC ‐ HIF ‐1 α ‐null mice. Isoflurane‐induced  DCI  protection was attenuated in 2 ME 2‐treated  WT  mice and  EC ‐ HIF ‐1 α ‐null mice.    Interpretation  Isoflurane postconditioning provides strong  HIF ‐1 α ‐mediated macro‐ and microvascular protection in  SAH , leading to improved neurological outcome. These results implicate cerebral vessels as a key target for the brain protection afforded by isoflurane postconditioning, and  HIF ‐1 α  as a critical mediator of this vascular protection. They also identify isoflurane postconditioning as a promising novel therapeutic for  SAH .

HIF‐1α Mediates Isoflurane‐Induced Vascular Protection in Subarachnoid Hemorrhage