GENE-TRANSFER OF NAKED DNA ENCODING FOR 3 ISOFORMS OF VASCULAR ENDOTHELIAL GROWTH-FACTOR STIMULATES COLLATERAL DEVELOPMENT IN-VIVO

Vascular endothelial growth factor (VEGF) is a naturally secreted endo thelial cell-specific mitogen. We investigated the hypothesis that nak ed DNA encoding for VEGF could be used in a strategy of arterial gene therapy to stimulate collateral artery development. Plasmid DNA encodi ng each of the three principal human VEGF isoforms (phVEGF(121), phVEG F(165), or phVEGF(189)) was applied to the hydrogel polymer coating of an angioplasty balloon and delivered percutaneously to one iliac arte ry of rabbits with operatively induced hindlimb ischemia. Compared wit h control animals transfected with LacZ, site-specific transfection of phVEGF resulted in augmented collateral vessel development documented by serial angiography, and improvement in calf blood pressure ratio ( ischemic to normal limb), resting and maximum blood flow, and capillar y to myocyte ratio. Similar results were obtained with phVEGF(121), ph VEGF(165), and phVEGF(189), which suggests that these isoforms are bio logically equivalent with respect to in vivo angiogenesis. The fact th at viral or other adjunctive vectors were not required further suggest s that secreted gene products may have potential therapeutic utility e ven when the number of successfully transfected cells remains low. Art erial gene transfer of naked DNA encoding for a secreted angiogenic cy tokine, thus, represents a potential alternative to recombinant protei n administration for stimulating collateral vessel development.