title: Cerebral microcirculatory failure after subarachnoid hemorrhage is reversed by hyaluronidase.
abstract: Aneurysmal subarachnoid hemorrhage remains one of the more devastating forms of stroke due in large part to delayed cerebral ischemia that appears days to weeks following the initial hemorrhage. Therapies exclusively targeting large caliber arterial vasospasm have fallen short, and thus we asked whether capillary dysfunction contributes to delayed cerebral ischemia after subarachnoid hemorrhage. Using a mouse model of subarachnoid hemorrhage and two-photon microscopy we showed capillary dysfunction unrelated to upstream arterial constriction. Subarachnoid hemorrhage decreased RBC velocity by 30%, decreased capillary pulsatility by 50%, and increased length of non-perfusing capillaries by 15%. This was accompanied by severe brain hypoxia and neuronal loss. Hyaluronidase, an enzyme that alters capillary blood flow by removing the luminal glycocalyx, returned RBC velocity and pulsatility to normal. Hyaluronidase also reversed brain hypoxia and prevented neuron loss typically seen after subarachnoid hemorrhage. Thus, subarachnoid hemorrhage causes specific changes in capillary RBC flow independent of arterial spasm, and hyaluronidase treatment that normalizes capillary blood flow can prevent brain hypoxia and injury after subarachnoid hemorrhage. Prevention or treatment of capillary dysfunction after subarachnoid hemorrhage may reduce the incidence or severity of subarachnoid hemorrhage-induced delayed cerebral ischemia.
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, University of Rochester Medical Center, Rochester, NY, USA Department of Neurological Surgery, University of Rochester Medical Center, Rochester, NY, USA evan_mcconnell@urmc.rochester.edu.
authors.forename: Evan D
authors.initials: ED
authors.lastname: McConnell
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, University of Rochester Medical Center, Rochester, NY, USA Department of Neurological Surgery, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Helen S
authors.initials: HS
authors.lastname: Wei
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, University of Rochester Medical Center, Rochester, NY, USA Department of Neurological Surgery, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Reitz
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, University of Rochester Medical Center, Rochester, NY, USA Department of Neurological Surgery, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Hongyi
authors.initials: H
authors.lastname: Kang
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, University of Rochester Medical Center, Rochester, NY, USA Department of Neurological Surgery, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Takano
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, University of Rochester Medical Center, Rochester, NY, USA Department of Neurological Surgery, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: G Edward
authors.initials: GE
authors.lastname: Vates
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, University of Rochester Medical Center, Rochester, NY, USA Department of Neurological Surgery, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000517:prevention & control; D002196:Capillaries / Q000187:drug effects / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D006821:Hyaluronoglucosaminidase / Q000627:therapeutic use*; D000860:Hypoxia / Q000517:prevention & control; D051379:Mice; D008833:Microcirculation / Q000187:drug effects*; D013345:Subarachnoid Hemorrhage / Q000503:physiopathology*
chemical_list: D006821:Hyaluronoglucosaminidase
keywords: Capillaries; cerebral blood flow; cerebrovascular disease; subarachnoid hemorrhage; two-photon microscopy