SITE-SPECIFIC THERAPEUTIC ANGIOGENESIS AFTER SYSTEMIC ADMINISTRATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR

Purpose: Recent experimental studies have established the feasibility of therapeutic angiogenesis; in all cases, this has been achieved with local administration of angiogenic growth factors. This study was des igned to investigate the hypothesis that systemic administration of an angiogenic growth factor specifically mitogenic for endothelial cells -vascular endothelial growth factor (VEGF)-could augment collateral ve ssel development in a rabbit ischemic hindlimb model. Methods: Ten day s after the Ligation of the external iliac artery and excision of the common and superficial femoral arteries in one limb of New Zealand whi te rabbits, heparin (800 IU, n = 13), VEGF (1 mg, n = 3; 5 mg, n = 5), heparin (800 IU) + VEGF (1 mg, n = 5; 5 mg, n = 7), or saline solutio n (n = 8) was injected as a single bolus in a marginal ear vein. Colla teral vessel formation and limb perfusion were assessed 10 and 30 days after treatment. Results: Animals in both VEGF-treated groups had a s ignificantly higher (p < 0.01) increase in calfblood pressure ratio at day 10 (control, 0.44 +/- 0.02; heparin, 0.47 +/- 0.02; VEGF, 0.60 +/ - 0.01; heparin + VEGF, 0.61 +/- 0.02) and day 30 (control, 0.49 +/- 0 .05; heparin, 0.48 +/- 0.02; VEGF, 0.70 +/- 0.03; heparin + VEGF, 0.73 +/- 0.03). Both VEGF-treated groups had a significantly higher (p < 0 .05) angiographic score at day 30 (control, 0.28 +/- 0.01; heparin, 0. 28 +/- 0.01; VEGF, 0.37 +/- 0.01; heparin +/- VEGF, 0.38 +/- 0.02). Ma ximum flow reserve at day 30 in the ischemic limb was higher (p < 0.05 ) in VEGF-treated rabbits (control, 1.87 +/- 0.07; heparin, 1.92 +/- 0 .08; VEGF, 2.42 +/- 0.16; heparin +/- VEGF, 2.33 +/- 0.12). Capillary density was higher (p < 0.01) in the ischemic muscles of VEGF-treated rabbits (control, 156 +/- 10/mm(2); heparin, 178 +/- 8/mm(2); VEGF, 23 0 +/- 10/mm(2); heparin + VEGF, 233 +/- 8/mm(2)). Conclusions: This se ries of in vivo experiments demonstrates that intravenous administrati on of VEGF, with or without heparin, results in both anatomic and phys iologic evidence of enhanced collateral vessel formation in the rabbit ischemic hindlimb. Single-bolus systemic administration of VEGF may b e a feasible therapeutic strategy in patients with lower-extremity isc hemia.