Combined sustained delivery of basic fibroblast growth factor and administration of granulocyte colony-stimulating factor: Synergistic effect on angiogenesis in mouse ischemic limbs

Purpose: To investigate whether the efficacy of a single angiogenic therapy (sustained delivery of basic fibroblast growth factor [bFGF] or administration of granulocyte colony-stimulating factor [G-CSF]) can be enhanced further by combining the therapies. Methods: One day after surgical induction of hind-limb ischemia, groups of 6 mice were randomized to receive either no treatment, sustained delivery (SD) of bFGF, endothelial progenitor cell (EPC) mobilization with G-CSF administration, or a combination of bFGF SD+G-CSF administration. Results: G-CSF administration increased significantly (p<0.05) the number of EPC lineages (CD34+/AC133+ cells) in both peripheral blood and bone marrow compared to no G-CSF administration. The bFGF SD and G-CSF administration individually increased the capillary and arteriole densities significantly versus no treatment (capillary density: 659 +/- 48/mm(2) and 385 +/- 59/mm(2), respectively, versus 280 +/- 28/mm(2); p<0.05; arteriole density: 34 +/- 9/mm(2) and 41 +/- 6/mm(2), respectively, versus 15 +/- 2/mm(2); p<0.05). Importantly, bFGF SD+G-CSF further increased the capillary and arteriole densities compared to either strategy alone (capillary density: 786 +/- 40/mm(2) versus 659 +/- 48/mm(2) and 385 +/- 59/mm(2), respectively, p<0.05; arteriole density: 55 +/- 10/mm(2) versus 34 +/- 9/mm(2) and 41 +/- 6/mm(2), respectively, p<0.05). Conclusion: This study demonstrates that the combined therapy of sustained bFGF delivery and G-CSF administration potentiates the angiogenic efficacy of either single therapy in mouse hind-limb ischemia models.