Therapeutically induced focal angiogenesis will provide a unique approach to rescue ischemic injured brain tissue, and improve neurological outcome. The associated adverse effects such as vascular leakage and edema compromise VEGF as a therapeutic agent for stroke intervention. Developmental endothelial locus-1 (Del-1) is a novel angiomatrix protein, which has been demonstrated to stimulate a potent angiogenic response, and promote functional recovery in hind limb and cardiac ischemia in vivo. Whether Del-1 is expressed in the normal or ischemic brain, and what functions Del-1 plays in the ischemic brain has not been investigated. The effect of Del-1 hyperstimulation in the brain is unknown. Our general hypothesis is that Del-1 overexpression through gene transfer, compared to VEGF overexpression, induces functional cerebral angiogenesis, but with retained barrier function, thereby improving neurological outcome. Specifically, we will determine whether overexpression of Del-1 by gene transfer stimulates functional brain angiogenesis, and reduces neurological deficits in a mouse model of transient middle cerebral artery occlusion (tMCAO). Microvessel counting, BBB permeability, focal cerebral blood flow, and tight junction protein ZO-1 expression will be used to assess functional neovessel formation. We will also investigate the mechanisms by which Del-1 induces focal angiogenesis in the mouse brain. Del-1 has an Arg-Gly-Asp motif and has been shown to mediate migration of endothelial cells through integrin binding. The primary pathways of Del-1 induced angiogenesis will be investigated by using avB3 and avB5 integrin knockout mice, as well as a series of function-blocking antibodies, and rescue strategies. Whether transcription factor HoxD3, which is a potent proangiogenic factor, is required for Del-1 induced angiogenesis will also be examined by using HoxDS RNA silencing. The results from this study may lead to the development of a clinically significant stroke therapy. ? ? ?
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