Abstract 14398: Prolyl Hydroxylase 1 Silencing Promotes Angiogenesis and Improves Blood Perfusion in a Mouse Hind-Limb Ischemia Model: A Gene Knockout Study
INTRODUCTION: Development of effective strategies in treating Peripheral Arterial Disease (PAD) increasingly requires a molecular approach. Prolyl hydroxylase domain proteins (PHD 1-3) are known to play a role in ischemia-induced neovascularization through the modulation of Hypoxia inducible factor (HIF). We explored whether homozygous disruption of PHD1 (-/-) would result in amplified ischemia-induced neovascularization in a mouse model of hind limb ischemia (HLI). METHODS: Ischemia-induced neovascularization was studied in 8-12 week old Wild type (WT) and PHD1 Knockout (PHD1KO) mice. Following ligation of the right femoral artery, mice were observed serially over a period of 4 weeks by Laser Doppler Imaging. Muscle tissue was subjected to immunohistochemistry to determine the extent of angiogenesis, arteriogenesis and VEGF expression. RESULTS: PHD1KO mice showed significant recovery of blood perfusion when compared to WT mice at post-operative day 3 [0.33±0.06(N=10) vs. 0.19±0.03(N=19); p<0.05] till day 28 [0.82±0.11(N=15) vs. 0.54±0.06(N=15); p<0.05] (Figure 1) and a higher motor function score from day 7 [3.66±0.18(N=15) vs. 2.94±0.17(N=18); p<0.05] till day 28 [5±0(N=15) vs. 4.53±0.21(N=15); p<0.05]. We observed increased capillary density [1902±101.6 (N=8) vs. 727.72±63.59 (N=6) counts/mm2; p<0.05], arteriolar density [22.31±1.55 (N=6) vs. 13.59±0.88 (N=6) counts/mm2; p<0.05] and capillary/myocyte ratio [2.21±0.12 (N=8) vs. 1.29± 0.10(N=6); p<0.05] in PHD1KO mice compared to WT mice. Immunohistological analysis documented increased VEGF expression in PHD1KO vs WT. CONCLUSION(S): These results demonstrate for the first time that knocking down PHD1 domain enhances VEGF expression and improves ischemia-induced neovascularization and blood perfusion in a mouse model of HLI offering a potential, new therapeutic approach in the treatment of PAD.
- © 2012 by American Heart Association, Inc.