Angiogenesis is a physiologic process in which new blood vessels are formed to meet the oxygen demands of local tissues. With the identification of specific biologic mediators of angiogenesis it is now possible to consider ~therapeutic angiogenesis,~ where angiogenic molecules could be administered to develop new vascular networks to circumvent the ischemic consequences of atherosclerosis occluding the arterial system. The focus of this proposal is to study the angiogenesis-related in vitro an in vivo biology of the potent angiogenesis mediator vascular endothelial growth factor (VEGF) when it is delivered in the form of a cDNA using replication deficient recombinant adenovirus (Ad) vectors. The VEGF gene is naturally expressed through alternative splicing as four mRNA transcripts, coding for secreted proteins of 206, 189, 165, and 121 residues, each with different bioavailability secondary to different associations with the extracellular matrix. The VEGF proteins exert their function almost exclusively on endothelia cells through two specific receptors, flt-1 and KDR/flk-1. In the context of our plans to develop a human gene therapy study using adenovirus vector-mediated transfer to the VEGF-related genes for the treatment of diffuse atherosclerosis, the specific aims of this proposal are focused on: the characterization of the angiogenic response of the four VEGF isoforms delivered with Ad vector; evaluating the consequences of providing VEGF to tissues after Ad vectors have been used to transfer the cDNAs for the VEGF receptors to the endothelium; and examining whether modification of the serotype of the Ad capsid will escape anti-Ad vector recognition by neutralizing antibodies, thus permitting repetitive Ad vector-mediated VEGF or VEGF receptor gene transfer and expression in order to evoke localized angiogenesis as needed. Results of these studies will help define gene therapy strategies for therapeutic angiogenesis for the treatment of atherosclerosis.
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