Open AccessHIF‐1α Mediates Isoflurane‐Induced Vascular Protection in Subarachnoid Hemorrhage
Author(s) -
Milner Eric,
Johnson Andrew W.,
Nelson James W.,
Harries Michael D.,
Gidday Jeffrey M.,
Han Byung Hee,
Zipfel Gregory J.
Publication year - 2015
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.170
Subject(s) - medicine , subarachnoid hemorrhage , isoflurane , vasospasm , cerebral vasospasm , anesthesia , ischemia , neuroprotection , thrombosis , vasoconstriction , pharmacology
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 .