Vascular endothelial growth factor is increased in cerebrospinal fluid after traumatic brain injury in infants and children.
OBJECTIVE
Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis, the formation of which is triggered by hypoxia, cytokines, and growth factors and is also induced by activation of the adenosine 2B receptor. VEGF is neuroprotective in several models of experimental brain injury and is increased in brain after traumatic brain injury (TBI) in humans and experimental animals. Adenosine is a neuroprotective purine metabolite that increases in cerebrospinal fluid (CSF) after clinical TBI in children. We hypothesized that VEGF levels would 1). be increased in CSF after TBI in infants and children, and 2). be preceded by increases in CSF adenosine. To test this hypothesis, we designed a case-control study to compare the CSF of infants and children after severe TBI with that of uninjured children.


METHODS
Using an Institutional Review Board-approved protocol, we compared CSF concentrations of VEGF (by enzyme-linked immunosorbent assay) and adenosine (by high-performance liquid chromatography) in 73 samples from 14 infants and children with severe TBI (Glasgow Coma Scale score <or=8) with those in CSF from 5 noninjured control subjects. Patients received standard neurointensive care.


RESULTS
Mean VEGF levels were increased after TBI versus control (39.8 +/- 6.2 versus 14.9 +/- 1.5 ng/dl, mean +/- standard error of the mean, P = 0.0002) and peaked at 91.6 +/- 26.4 ng/dl, approximately 6 times control (P = 0.001). Peak VEGF occurred at 22.4 hours after injury. There was a trend toward increased adenosine concentration after TBI versus control (18.3 +/- 3.5 versus 11.5 +/- 2.3 nmol/L), but this did not reach statistical significance. A multivariate regression model showed an independent, significant association between the concentrations of VEGF and adenosine.


CONCLUSIONS
VEGF is increased in CSF after pediatric TBI, and this increase is associated with an increase in CSF adenosine. These results may imply that a component of the vascular regenerative response of the brain is initiated rapidly after TBI and continues for several days after injury. Further investigation is warranted to determine 1). whether this association is causative, 2). the role of adenosine in triggering the increase in CSF VEGF concentration, and 3). the exact role VEGF that plays after injury.
Shore
Paul M
PM
Department of Critical Care Medicine, University of Pittsburgh School of Medicine and Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Jackson
Edwin K
EK
Wisniewski
Stephen R
SR
Clark
Robert S B
RS
Adelson
P David
PD
Kochanek
Patrick M
PM
D000241:Adenosine / Q000134:cerebrospinal fluid; D000293:Adolescent; D001930:Brain Injuries / Q000134:cerebrospinal fluid*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015600:Glasgow Coma Scale; D006801:Humans; D007223:Infant; D008297:Male; D011446:Prospective Studies; D012016:Reference Values; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*
D042461:Vascular Endothelial Growth Factor A; D000241:Adenosine