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.
| Shih, Andy Y; Nishimura, Nozomi; Nguyen, John et al. (2013) Optically induced occlusion of single blood vessels in rodent neocortex. Cold Spring Harb Protoc 2013:1153-60 |
| Chen, Bo; Van Winkle, Jessica A; Lyden, Patrick D et al. (2013) PHLPP1 gene deletion protects the brain from ischemic injury. J Cereb Blood Flow Metab 33:196-204 |
| Chen, Bo; Cheng, Qun; Yang, Kai et al. (2010) Thrombin mediates severe neurovascular injury during ischemia. Stroke 41:2348-52 |
| Tsai, Philbert S; Kaufhold, John P; Blinder, Pablo et al. (2009) Correlations of neuronal and microvascular densities in murine cortex revealed by direct counting and colocalization of nuclei and vessels. J Neurosci 29:14553-70 |
| Chen, Bo; Friedman, Beth; Cheng, Qun et al. (2009) Severe blood-brain barrier disruption and surrounding tissue injury. Stroke 40:e666-74 |
| Friedman, Beth; Schachtrup, Christian; Tsai, Philbert S et al. (2009) Acute vascular disruption and aquaporin 4 loss after stroke. Stroke 40:2182-90 |
| 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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