title: Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice.
abstract: Cerebral ischemia is a significant source of morbidity in children with sickle cell anemia; however, the mechanism of injury is poorly understood. Increased cerebral blood flow and low hemoglobin levels in children with sickle cell anemia are associated with increased stroke risk, suggesting that anemia-induced tissue hypoxia may be an important factor contributing to subsequent morbidity. To better understand the pathophysiology of brain injury, brain physiology and morphology were characterized in a transgenic mouse model, the Townes sickle cell model. Relative to age-matched controls, sickle cell anemia mice demonstrated: (1) decreased brain tissue pO2and increased expression of hypoxia signaling protein in the perivascular regions of the cerebral cortex; (2) elevated basal cerebral blood flow , consistent with adaptation to anemia-induced tissue hypoxia; (3) significant reduction in cerebrovascular blood flow reactivity to a hypercapnic challenge; (4) increased diameter of the carotid artery; and (5) significant volume changes in white and gray matter regions in the brain, as assessed by ex vivo magnetic resonance imaging. Collectively, these findings support the hypothesis that brain tissue hypoxia contributes to adaptive physiological and anatomic changes in Townes sickle cell mice. These findings may help define the pathophysiology for stroke in children with sickle cell anemia.
authors.affiliation: 1 Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Lindsay S
authors.initials: LS
authors.lastname: Cahill
authors.affiliation: 1 Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Gazdzinski
authors.affiliation: 2 Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Department of Anesthesia, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Albert Ky
authors.initials: AK
authors.lastname: Tsui
authors.affiliation: 1 Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Zhou
authors.affiliation: 1 Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Sharon
authors.initials: S
authors.lastname: Portnoy
authors.affiliation: 2 Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Department of Anesthesia, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Elaine
authors.initials: E
authors.lastname: Liu
authors.affiliation: 2 Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Department of Anesthesia, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.|3 Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: C David
authors.initials: CD
authors.lastname: Mazer
authors.affiliation: 2 Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Department of Anesthesia, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.|3 Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gregory Mt
authors.initials: GM
authors.lastname: Hare
authors.affiliation: 4 Department of Medical Imaging, University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kassner
authors.affiliation: 1 Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|5 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: John G
authors.initials: JG
authors.lastname: Sled
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000209:etiology; D002339:Carotid Arteries / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000502:physiology; D066128:Gray Matter / Q000473:pathology; D002534:Hypoxia, Brain / Q000150:complications / Q000209:etiology / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D020521:Stroke / Q000209:etiology; D066127:White Matter / Q000473:pathology
keywords: Sickle cell anemia mice; cerebral hypoxia; cerebrovascular reactivity; continuous arterial spin labelling MRI