ADENOVIRAL VECTORS FOR DELIVERY OF ANGIOGENIC CYTOKINES

Beth Israel Deaconess Medical Center, Boston MA

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Abstract

DESCRIPTION: Angiogenesis has a central role in many important disease processes, and it is widely anticipated that stimulation of angiogenesis in vascular insufficiency will provide important therapeutic benefits. Many different cytokines and growth factors express angiogenic activity but vascular permeability factor/vascular endothelial growth factor (VPFNEGF) stands out because of its potency, selectivity for vascular endothelium, and its importance in vasculogenesis and both pathological and physiological angiogenesis. Our long term goal is to use angiogenic cytokines to generate new, structurally and functionally mature blood vessels in ischemic tissues. Before this goal can be realized, much needs to be learned about the basic steps and mechanisms by which cytokines and particularly VPFNEGF induce new blood vessels in adult tissues. To investigate these mechanisms, we will use adenoviral vectors to express murine VPFNEGF164, its 122 and 188 amino acid isoforms, and certain functionally altered mutant VPFNEGFs in both normal and ischemic tissues of immunodeficient mice. We will characterize the structure, function and organization of the new vessels that form; investigate the basis for tissue specificity of the angiogenic response; elucidate the mechanisms by which VPFNEGF induces mother vessels, capillaries and muscular arteries/veins; and determine the origins, character and fate of glomeruloid bodies. Our specific aims are as follows: 1. Define the mechanisms by which VPF/VEGF164 induces different types of new blood vessels in normal adult tissues. Structure, function and organization of the new vessels. 2. Characterize the angiogenic responses induced by the 120 and 188 amino acid isoforms of VPFNEGF and by function-altered VPF/VEGF mutants. 3. Elucidate the mechanisms responsible for the tissue specificity of the angiogenic response induced by VPF/VEGF164. Define the origins, character and fate of glomeruloid bodies. 4.Compare the angiogenic response to ischemia with that induced by VPFNEGF164 and its 120 and 188 amino acid isoforms in ischemic and non-ischemic tissues.