title: Astrocyte-Derived Pentraxin 3 Supports Blood-Brain Barrier Integrity Under Acute Phase of Stroke.
abstract: OBJECTIVE
  Pentraxin 3 (PTX3) is released on inflammatory responses in many organs. However, roles of PTX3 in brain are still mostly unknown. Here we asked whether and how PTX3 contributes to blood-brain barrier dysfunction during the acute phase of ischemic stroke.
  
  
  METHODS
  In vivo, spontaneously hypertensive rats were subjected to focal cerebral ischemia by transient middle cerebral artery occlusion. At day 3, brains were analyzed to evaluate the cellular origin of PTX3 expression. Correlations with blood-brain barrier breakdown were assessed by IgG staining. In vitro, rat primary astrocytes and rat brain endothelial RBE.4 cells were cultured to study the role of astrocyte-derived PTX3 on vascular endothelial growth factor-mediated endothelial permeability.
  
  
  RESULTS
  During the acute phase of stroke, reactive astrocytes in the peri-infarct area expressed PTX3. There was negative correlation between gradients of IgG leakage and PTX3-positive astrocytes. Cell culture experiments showed that astrocyte-conditioned media increased levels of tight junction proteins and reduced endothelial permeability under normal conditions. Removing PTX3 from astrocyte-conditioned media by immunoprecipitation increased endothelial permeability. PTX3 strongly bound vascular endothelial growth factor in vitro and was able to decrease vascular endothelial growth factor-induced endothelial permeability.
  
  
  CONCLUSIONS
  Astrocytes in peri-infarct areas upregulate PTX3, which may support blood-brain barrier integrity by regulating vascular endothelial growth factor-related mechanisms. This response in astrocytes may comprise a compensatory mechanism for maintaining blood-brain barrier function after ischemic stroke.
authors.affiliation: From the Neuroprotection Research Laboratory, Departments of Radiology and Neurology (A.S., T.M., E.T.M., A.C.L., N.E., K.I., N.I., M.B., J.L., E.H.L., K.A.) and Pediatrics (J.L.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Boston; Department of Vascular Biology, GlaxoSmithKline, Harlow, United Kingdom (J.C.H., T.T.C., J.D.M.); and Department of Neurology, Mie University Graduate School of Medicine, Mie, Japan (A.S., H.T.).
authors.forename: Akihiro
authors.initials: A
authors.lastname: Shindo
authors.affiliation: From the Neuroprotection Research Laboratory, Departments of Radiology and Neurology (A.S., T.M., E.T.M., A.C.L., N.E., K.I., N.I., M.B., J.L., E.H.L., K.A.) and Pediatrics (J.L.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Boston; Department of Vascular Biology, GlaxoSmithKline, Harlow, United Kingdom (J.C.H., T.T.C., J.D.M.); and Department of Neurology, Mie University Graduate School of Medicine, Mie, Japan (A.S., H.T.).
authors.forename: Takakuni
authors.initials: T
authors.lastname: Maki
authors.affiliation: From the Neuroprotection Research Laboratory, Departments of Radiology and Neurology (A.S., T.M., E.T.M., A.C.L., N.E., K.I., N.I., M.B., J.L., E.H.L., K.A.) and Pediatrics (J.L.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Boston; Department of Vascular Biology, GlaxoSmithKline, Harlow, United Kingdom (J.C.H., T.T.C., J.D.M.); and Department of Neurology, Mie University Graduate School of Medicine, Mie, Japan (A.S., H.T.).
authors.forename: Emiri T
authors.initials: ET
authors.lastname: Mandeville
authors.affiliation: From the Neuroprotection Research Laboratory, Departments of Radiology and Neurology (A.S., T.M., E.T.M., A.C.L., N.E., K.I., N.I., M.B., J.L., E.H.L., K.A.) and Pediatrics (J.L.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Boston; Department of Vascular Biology, GlaxoSmithKline, Harlow, United Kingdom (J.C.H., T.T.C., J.D.M.); and Department of Neurology, Mie University Graduate School of Medicine, Mie, Japan (A.S., H.T.).
authors.forename: Anna C
authors.initials: AC
authors.lastname: Liang
authors.affiliation: From the Neuroprotection Research Laboratory, Departments of Radiology and Neurology (A.S., T.M., E.T.M., A.C.L., N.E., K.I., N.I., M.B., J.L., E.H.L., K.A.) and Pediatrics (J.L.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Boston; Department of Vascular Biology, GlaxoSmithKline, Harlow, United Kingdom (J.C.H., T.T.C., J.D.M.); and Department of Neurology, Mie University Graduate School of Medicine, Mie, Japan (A.S., H.T.).
authors.forename: Naohiro
authors.initials: N
authors.lastname: Egawa
authors.affiliation: From the Neuroprotection Research Laboratory, Departments of Radiology and Neurology (A.S., T.M., E.T.M., A.C.L., N.E., K.I., N.I., M.B., J.L., E.H.L., K.A.) and Pediatrics (J.L.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Boston; Department of Vascular Biology, GlaxoSmithKline, Harlow, United Kingdom (J.C.H., T.T.C., J.D.M.); and Department of Neurology, Mie University Graduate School of Medicine, Mie, Japan (A.S., H.T.).
authors.forename: Kanako
authors.initials: K
authors.lastname: Itoh
authors.affiliation: From the Neuroprotection Research Laboratory, Departments of Radiology and Neurology (A.S., T.M., E.T.M., A.C.L., N.E., K.I., N.I., M.B., J.L., E.H.L., K.A.) and Pediatrics (J.L.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Boston; Department of Vascular Biology, GlaxoSmithKline, Harlow, United Kingdom (J.C.H., T.T.C., J.D.M.); and Department of Neurology, Mie University Graduate School of Medicine, Mie, Japan (A.S., H.T.).
authors.forename: Naoki
authors.initials: N
authors.lastname: Itoh
authors.affiliation: From the Neuroprotection Research Laboratory, Departments of Radiology and Neurology (A.S., T.M., E.T.M., A.C.L., N.E., K.I., N.I., M.B., J.L., E.H.L., K.A.) and Pediatrics (J.L.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Boston; Department of Vascular Biology, GlaxoSmithKline, Harlow, United Kingdom (J.C.H., T.T.C., J.D.M.); and Department of Neurology, Mie University Graduate School of Medicine, Mie, Japan (A.S., H.T.).
authors.forename: Mia
authors.initials: M
authors.lastname: Borlongan
authors.affiliation: From the Neuroprotection Research Laboratory, Departments of Radiology and Neurology (A.S., T.M., E.T.M., A.C.L., N.E., K.I., N.I., M.B., J.L., E.H.L., K.A.) and Pediatrics (J.L.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Boston; Department of Vascular Biology, GlaxoSmithKline, Harlow, United Kingdom (J.C.H., T.T.C., J.D.M.); and Department of Neurology, Mie University Graduate School of Medicine, Mie, Japan (A.S., H.T.).
authors.forename: Julie C
authors.initials: JC
authors.lastname: Holder
authors.affiliation: From the Neuroprotection Research Laboratory, Departments of Radiology and Neurology (A.S., T.M., E.T.M., A.C.L., N.E., K.I., N.I., M.B., J.L., E.H.L., K.A.) and Pediatrics (J.L.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Boston; Department of Vascular Biology, GlaxoSmithKline, Harlow, United Kingdom (J.C.H., T.T.C., J.D.M.); and Department of Neurology, Mie University Graduate School of Medicine, Mie, Japan (A.S., H.T.).
authors.forename: Tsu Tshen
authors.initials: TT
authors.lastname: Chuang
authors.affiliation: From the Neuroprotection Research Laboratory, Departments of Radiology and Neurology (A.S., T.M., E.T.M., A.C.L., N.E., K.I., N.I., M.B., J.L., E.H.L., K.A.) and Pediatrics (J.L.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Boston; Department of Vascular Biology, GlaxoSmithKline, Harlow, United Kingdom (J.C.H., T.T.C., J.D.M.); and Department of Neurology, Mie University Graduate School of Medicine, Mie, Japan (A.S., H.T.).
authors.forename: John D
authors.initials: JD
authors.lastname: McNeish
authors.affiliation: From the Neuroprotection Research Laboratory, Departments of Radiology and Neurology (A.S., T.M., E.T.M., A.C.L., N.E., K.I., N.I., M.B., J.L., E.H.L., K.A.) and Pediatrics (J.L.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Boston; Department of Vascular Biology, GlaxoSmithKline, Harlow, United Kingdom (J.C.H., T.T.C., J.D.M.); and Department of Neurology, Mie University Graduate School of Medicine, Mie, Japan (A.S., H.T.).
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tomimoto
authors.affiliation: From the Neuroprotection Research Laboratory, Departments of Radiology and Neurology (A.S., T.M., E.T.M., A.C.L., N.E., K.I., N.I., M.B., J.L., E.H.L., K.A.) and Pediatrics (J.L.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Boston; Department of Vascular Biology, GlaxoSmithKline, Harlow, United Kingdom (J.C.H., T.T.C., J.D.M.); and Department of Neurology, Mie University Graduate School of Medicine, Mie, Japan (A.S., H.T.).
authors.forename: Josephine
authors.initials: J
authors.lastname: Lok
authors.affiliation: From the Neuroprotection Research Laboratory, Departments of Radiology and Neurology (A.S., T.M., E.T.M., A.C.L., N.E., K.I., N.I., M.B., J.L., E.H.L., K.A.) and Pediatrics (J.L.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Boston; Department of Vascular Biology, GlaxoSmithKline, Harlow, United Kingdom (J.C.H., T.T.C., J.D.M.); and Department of Neurology, Mie University Graduate School of Medicine, Mie, Japan (A.S., H.T.).
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.affiliation: From the Neuroprotection Research Laboratory, Departments of Radiology and Neurology (A.S., T.M., E.T.M., A.C.L., N.E., K.I., N.I., M.B., J.L., E.H.L., K.A.) and Pediatrics (J.L.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Boston; Department of Vascular Biology, GlaxoSmithKline, Harlow, United Kingdom (J.C.H., T.T.C., J.D.M.); and Department of Neurology, Mie University Graduate School of Medicine, Mie, Japan (A.S., H.T.). karai@partners.org.
authors.forename: Ken
authors.initials: K
authors.lastname: Arai
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002097:C-Reactive Protein / Q000378:metabolism*; D016923:Cell Death; D017077:Culture Media, Conditioned; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D000683:Serum Amyloid P-Component / Q000378:metabolism*; D020521:Stroke / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D017077:Culture Media, Conditioned; D000683:Serum Amyloid P-Component; D042461:Vascular Endothelial Growth Factor A; D000099153:Pentraxins
keywords: astrocyte; blood–brain barrier; cell–cell interaction; endothelium; stroke