Although peptide angiogenic signals may promote new vessel formation, may offer neuroprotection, and may facilitate neuronal migration during recovery, our pilot data suggests a different function after ischemia: the brain may utilize angiogenic signaling only to subserve removal of necrotic debris, i.e., """"""""clean-up"""""""". Our central hypothesis is that after ischemia, angiogenic growth factors are secreted to open blood brain barrier, stimulate macrophage infiltration, and to create vascular channels for removal of necrotic debris.
Our aims are: we will measure capillary and neuronal density 30 days after focal brain ischemia to establish whether ischemia stimulates persisting microvessels, preserves neurons, or both. Then we will determine if microvessel or neuronal densities can be augmented with intra-arterial infusions of VEGF or bFGF or both. Do Macrophages Influence the Growth of New Microvessls? We will block macrophage entry into the brain by depleting them (whole body irradiation) or inhibiting them (colchicine/chloroquine), and expect to see a marked reduction of both macrophages and microvessels near the ischemic zone. We will increase macrophage entry into the ischemic zone with tissue necrosis factor, macrophage inflammatory protein-I, or monocyte chemoattractant protein-1 and expect to find more microvessels and macrophages. We will inhibit VEGF activity immediately after ischemia with anti-VEGFR antibody, a VEGFR-Fc fusion protein, and a tyrosine kinase inhibitor specific for VEGFR. Does Angiopoietin-2 Signal Microvessel Degradation? We will provide VEGF beginning 10 days after stroke and continuing to 17 days after stroke, to blunt the degradation signal; we predict that microvessels will persist. We will administer a TIE-2 receptor-Fc binding protein from Day 10 to 17 after stroke to bind and remove TIE-2 ligands (especially Ang-2), again predicting that microvessels will persist. Does angiogenic signaling ameliorate cognitive deficit after stroke? Using a bioassay suited to studying pharmacological synergism, we will study protective effects of VEGF, bFGF, or both using a bioassay and a spatial navigation test.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS043300-01A1
Application #
6575479
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Jacobs, Tom P
Project Start
2002-12-15
Project End
2006-11-30
Budget Start
2002-12-15
Budget End
2003-11-30
Support Year
1
Fiscal Year
2003
Total Cost
$267,330
Indirect Cost
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
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Yu, Sung Wook; Friedman, Beth; Cheng, Qun et al. (2007) Stroke-evoked angiogenesis results in a transient population of microvessels. J Cereb Blood Flow Metab 27:755-63
Nishimura, Nozomi; Schaffer, Chris B; Friedman, Beth et al. (2007) Penetrating arterioles are a bottleneck in the perfusion of neocortex. Proc Natl Acad Sci U S A 104:365-70
Nishimura, Nozomi; Schaffer, Chris B; Friedman, Beth et al. (2006) Targeted insult to subsurface cortical blood vessels using ultrashort laser pulses: three models of stroke. Nat Methods 3:99-108
Schaffer, Chris B; Friedman, Beth; Nishimura, Nozomi et al. (2006) Two-photon imaging of cortical surface microvessels reveals a robust redistribution in blood flow after vascular occlusion. PLoS Biol 4:e22

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