Vascular endothelial growth factor improves functional outcome and decreases secondary degeneration in experimental spinal cord contusion injury.
Spinal cord injury leads to acute local ischemia, which may contribute to secondary degeneration. Hypoxia stimulates angiogenesis through a cascade of events, involving angiogenesis stimulatory substances, such as vascular endothelial growth factor (VEGF). To test the importance of angiogenesis for functional outcome and wound healing in spinal cord injury VEGF165 (proangiogenic), Ringer's (control) or angiostatin (antiangiogenic) were delivered locally immediately after a contusion injury produced using the NYU impactor and a 25 mm weight-drop. Rats treated with VEGF showed significantly improved behavior up to 6 weeks after injury compared with control animals, while angiostatin treatment lead to no statistically significant changes in behavior outcome. Furthermore, VEGF-treated animals had an increased amount of spared tissue in the lesion center and a higher blood vessel density in parts of the wound area compared with controls. These effects were unlikely to be due to increased cell proliferation as determined by bromo-deoxy-uridine-labeling. Moreover, VEGF treatment led to decreased levels of apoptosis, as revealed by TUNEL assays. In situ hybridization demonstrated presence of mRNA for VEGF receptors Flt-1, fetal liver kinase-1, neuropilin-1 and -2 in several important cellular compartments of the spinal cord. The different experiments indicate that beneficial effects seen by acute VEGF delivery was attributable to protection/repair of blood vessels, decreased apoptosis and possibly also by other additional effects on glial cells or certain neuron populations.
Widenfalk
J
J
Department of Neuroscience, Karolinska Institutet, Retzius väg 8, B2,IV, S-171 77, Stockholm, Sweden. johan.widenfalk@neuro.ki.se
Lipson
A
A
Jubran
M
M
Hofstetter
C
C
Ebendal
T
T
Cao
Y
Y
Olson
L
L
D000704:Analysis of Variance; D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D043168:Angiostatins; D000818:Animals; D000831:Animals, Newborn; D000941:Antigens / Q000378:metabolism; D001253:Astrocytes; D001522:Behavior, Animal / Q000187:drug effects; D001808:Blood Vessels / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000493:pharmacokinetics; D002452:Cell Count; D016923:Cell Death; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D009410:Nerve Degeneration / Q000188:drug therapy*; D016900:Neurofilament Proteins / Q000378:metabolism; D039942:Neuropilin-1 / Q000235:genetics; D039943:Neuropilin-2 / Q000235:genetics; D010446:Peptide Fragments / Q000008:administration & dosage; D010958:Plasminogen / Q000008:administration & dosage; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors; D014945:Wound Healing; D014841:von Willebrand Factor / Q000276:immunology
D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D000941:Antigens; D016228:Endothelial Growth Factors; D016326:Extracellular Matrix Proteins; D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D016900:Neurofilament Proteins; D039943:Neuropilin-2; D010446:Peptide Fragments; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C029417:Von Willebrand antigen; D014841:von Willebrand Factor; C018588:Luxol Fast Blue MBS; D039942:Neuropilin-1; D043168:Angiostatins; D010958:Plasminogen; C501162:FLT1 protein, human; C501164:Flt1 protein, rat; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D001973:Bromodeoxyuridine