Repeated, but not single, VEGF gene transfer provides stable, long-lasting angiogenesis in rabbits with hindlimb ischemia

OLEA FD; HNATIUK A; CUNIBERTI L; MARZIALI L; VERA JANAVEL G; CABEZA MECKERT P; BERCOVICH A; CRISCUOLO M; LAGUENS R; CROTTOGINI A

Ciudad de Buenos Aires

Congreso; XVII Meeting International Society for Heart Research Latin American Section; 2009

International Society for Heart Research

VEGF gene transfer-mediated angiogenesis has been proposed for peripheral artery disease. Protocols using single administration have shown little benefit, likely because transient gene expression determines regression of the neovessels. Thus, repeated administration would be needed. Rabbits with hindlimb ischemia received 3.8 mg i.m. of a plasmid coding VEGF165 (pVEGF) at 7 (VEGF~1, n=10) or 7 and 21 days (VEGF~2, n=10). Placebo animals (n=10) received empty plasmid twice. Fifty days later, capillary density (CD) was 49.4}15.4 C/100 myocytes in G1, 84.6}14.7 in G2 (P<0.01 vs. G1 and G3, ANOVA + Bonferroni) and 49.3}13.6 in G3, and arteriolar density (AD) was 1.9}0.6 A/mm2 in G1, 3.0}0.9 in G2 (P<0.01 vs. G1 and G3) and 1.5}0.6 in G3. This pattern paralleled the time course of gene expression (RT-PCR, IHC), which peaked at 7 days and rapidly declined with VEGF~1, but remained positive at 50 days with VEGF~2. Ischemic muscle lesions were present in 60% of samples in placebo, 47% in VEGF~1 (P=NS vs. placebo, ƒÔ2 - Yates) and 25% in VEGF~2 (P=0.04 vs. placebo and VEGF~1).In additional rabbits studied at 90 days, CD and AD did not decrease in VEGF~2, although gene expression did, suggesting that neovascular stability resulting from repeated administration became partly independent from pVEGF expression. In conclusion, repeated, but not single, pVEGF165 transfer provides stable, long-lasting angiogenesis.