In this application, we propose to investigate the roles of vascular endothelial growth factor (VEGF) and angiopoietin 1 (Ang 1) in cerebral angiogenesis and blood brain barrier (BBB) leakage after focal cerebral embolic ischemia. Our preliminary data demonstrate that administration of VEGF at the time when endogenous Ang 1 is upregulated enhances angiogenesis in ischemic brain and improves functional recovery after stroke. Furthermore, an increase in levels of Ang 1 reduces BBB leakage after acute stroke. Our hypotheses are: 1) Co-administration of recombinant human VEGF165 (rhVEGF165) and BowAng 1, a forced Ang1 homodimer containing an Fc fusion protein, enhances angiogenesis and consequently improves neurological recovery. Enhancement of angiogenesis in ischemic brain promotes axonal and dendritic sprouting and synapse formation which leads to improved functional recovery; 2) VEGF and Ang 1 cooperatively maintain the integrity of BBB. An increase in levels of Ang 1 counteracts the effects of VEGF on vascular permeability and consequently decreases BBB leakage after stroke. The proposed experiments have been designed to test these hypotheses. We will first determine the effect of administration of rhVEGF165 and BowAng1 on cerebral angiogenesis and functional recovery after stroke. We will also investigate potential molecular and cellular mechanisms by which rhVEGF165 and BowAng1 treatments enhance functional recovery by measuring axonal and dendritic sprouting and synapse formation. Second, we will determine the effect of administration of BowAng1 on BBB leakage after ischemia. These studies will provide insights into roles of VEGF and Ang 1 in maintaining BBB integrity. Changes of BBB permeability, angiogenesis and axonal and dendritic sprouting will be measured by means of Magnetic Resonance Imaging, quantitative autoradiography, Laser Scanning Confocal Microscopy, and a novel software program for three-dimensional image analysis. We believe that these are unique and fresh approaches that may yield promising insights into the fundamental basis for angiogenic growth factors in controlling BBB integrity and angiogenesis and may lead to development of an effective restorative therapy for the treatment of ischemic stroke and cerebral edema.
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