title: Protective and detrimental effects of neuroectodermal cell-derived tissue factor in mouse models of stroke.
abstract: Within the CNS, a dysregulated hemostatic response contributes to both hemorrhagic and ischemic strokes. Tissue factor (TF), the primary initiator of the extrinsic coagulation cascade, plays an essential role in hemostasis and also contributes to thrombosis. Using both genetic and pharmacologic approaches, we characterized the contribution of neuroectodermal (NE) cell TF to the pathophysiology of stroke. We used mice with various levels of TF expression and found that astrocyte TF activity reduced to ~5% of WT levels was still sufficient to maintain hemostasis after hemorrhagic stroke but was also low enough to attenuate inflammation, reduce damage to the blood-brain barrier, and improve outcomes following ischemic stroke. Pharmacologic inhibition of TF during the reperfusion phase of ischemic stroke attenuated neuronal damage, improved behavioral deficit, and prevented mortality of mice. Our data demonstrate that NE cell TF limits bleeding complications associated with the transition from ischemic to hemorrhagic stroke and also contributes to the reperfusion injury after ischemic stroke. The high level of TF expression in the CNS is likely the result of selective pressure to limit intracerebral hemorrhage (ICH) after traumatic brain injury but, in the modern era, poses the additional risk of increased ischemia-reperfusion injury after ischemic stroke.
authors.affiliation: McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Shaobin
authors.initials: S
authors.lastname: Wang
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Brandi
authors.initials: B
authors.lastname: Reeves
authors.affiliation: McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Erica M
authors.initials: EM
authors.lastname: Sparkenbaugh
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Russell
authors.affiliation: Department of Neuroanatomy, Institute of Zoology, Jagiellonian University, Krakow, Poland.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Soltys
authors.affiliation: McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Faber
authors.affiliation: McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Nigel S
authors.initials: NS
authors.lastname: Key
authors.affiliation: Department of Early Discovery Biochemistry, Genentech Inc., South San Francisco, California, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kirchhofer
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
authors.forename: D Neil
authors.initials: DN
authors.lastname: Granger
authors.affiliation: McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
authors.affiliation: McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Rafal
authors.initials: R
authors.lastname: Pawlinski