title: Rescuing vasculature with intravenous angiopoietin-1 and alpha v beta 3 integrin peptide is protective after spinal cord injury.
abstract: Blood vessel loss and inflammation cause secondary degeneration following spinal cord injury. Angiopoietin-1 through the Tie2 receptor, and other ligands through alphavbeta3 integrin, promote endothelial cell survival during developmental or tumour angiogenesis. Here, daily intravenous injections with an alphavbeta3-binding peptide named C16 or an angiopoietin-1 mimetic following a spinal cord contusion at thoracic level 9 in mice rescued epicentre blood vessels, white matter and locomotor function, and reduced detrimental inflammation. Preserved vascularity and reduced inflammation correlated with improved outcomes. C16 and angiopoietin-1 reduced leukocyte transmigration in vitro. Growth factor receptors and integrins facilitate each others' function. Therefore, angiopoietin-1 and C16 were combined and the effects were additive, resulting in almost complete functional recovery. The treatment had lasting effects when started 4 h following injury and terminated after one week. These results identify alphavbeta3 integrin and the endothelial-selective angiopoietin-1 as vascular and inflammatory regulators that can be targeted in a clinically relevant manner for neuroprotection after central nervous system trauma.
authors.affiliation: Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, 511 S. Floyd St., MDR Building Room 616, University of Louisville, Louisville, KY 40292, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Han
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Arnold
authors.forename: Srinivas D
authors.initials: SD
authors.lastname: Sithu
authors.forename: Edward T
authors.initials: ET
authors.lastname: Mahoney
authors.forename: Justin T
authors.initials: JT
authors.lastname: Geralds
authors.forename: Phuong
authors.initials: P
authors.lastname: Tran
authors.forename: Richard L
authors.initials: RL
authors.lastname: Benton
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Maddie
authors.forename: Stanley E
authors.initials: SE
authors.lastname: D'Souza
authors.forename: Scott R
authors.initials: SR
authors.lastname: Whittemore
authors.forename: Theo
authors.initials: T
authors.lastname: Hagg
mesh_terms: D000595:Amino Acid Sequence; D042683:Angiopoietin-1 / Q000008:administration & dosage*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D039302:Integrin alphaVbeta3 / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010446:Peptide Fragments / Q000008:administration & dosage*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000098:blood supply* / Q000187:drug effects*; D013119:Spinal Cord Injuries / Q000503:physiopathology / Q000517:prevention & control*; D013904:Thoracic Vertebrae; D013997:Time Factors
chemical_list: D042683:Angiopoietin-1; D039302:Integrin alphaVbeta3; D018696:Neuroprotective Agents; D010446:Peptide Fragments