Contusive spinal cord injury (SCI) causes local endothelial cell damage, resulting in vascular leakage and edema and the initiation of inflammation. These processes may lead to later tissue loss and functional deficits. Vascular endothelial growth factor (VEGF) is induced by SCI and may contribute to the leakage. VEGF may initiate detrimental processes, as we have shown that VEGF injections after SCI in adult rats increases tissue loss seen at six weeks. Pharmacological inhibition of VEGF reduces edema, inflammation and tissue loss in stroke models. Angiopoietin 1 (Ang1) induces vessel maturation and reduces leakage in many systems and is reduced after SCI. Therefore, in aim la, a VEGF trap and/or Ang1 will be administered early after SCI to test whether reduction of early leakage, edema and inflammation reduces later loss of selected white matter tracts.
In aim lb) the contribution of endothelial cell loss to secondary damage will be evaluated by protecting the cells with Ang1 plus VEGF or integrin agonist, as these can promote endothelial cell survival in vitro. From 3-7 days after SCI, an angiogenic response occurs in the injured cord. New vessels may counteract degeneration by increased tissue perfusion, while their leakage may cause damage. Thus, in aim 2a, Ang1, will be administered during the angiogenic phase to promote maturation and maintenance of the new vasculature, possibly resulting in better tissue protection. The new blood vessels regress between day 7 and 14 as secondary spinal tissue loss (cavitation) begins. This angiogenic failure may contribute to the secondary damage.
In aim 2 b, the protective effects of maintaining the new blood vessels will be assessed by treating with Ang1 plus VEGF or Ang1 plus integrin agonist. The central hypothesis is that by enhancing stable and mature angiogenesis we will ultimately be able to reduce loss of important white matter tracts and improve functional sensory and motor outcome after SCI. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045734-02
Application #
6891637
Study Section
Special Emphasis Panel (ZRG1-CNNT (01))
Program Officer
Kleitman, Naomi
Project Start
2004-05-03
Project End
2009-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$336,780
Indirect Cost
Name
University of Louisville
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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