Rescuing vasculature with intravenous angiopoietin-1 and alpha v beta 3 integrin peptide is protective after spinal cord injury.
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.
Han
Shu
S
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.
Arnold
Sheila A
SA
Sithu
Srinivas D
SD
Mahoney
Edward T
ET
Geralds
Justin T
JT
Tran
Phuong
P
Benton
Richard L
RL
Maddie
Melissa A
MA
D'Souza
Stanley E
SE
Whittemore
Scott R
SR
Hagg
Theo
T
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
D042683:Angiopoietin-1; D039302:Integrin alphaVbeta3; D018696:Neuroprotective Agents; D010446:Peptide Fragments