Abstract 1226: The Fibroblast Growth Factor System Promotes Arteriogenesis
Background: Whereas studies have shown significant involvement of the fibroblast growth factor (FGF)-FGF receptor (FGFR) system in the post-ischemic neovascularization event, the precise contribution of the FGF system in arteriogenesis has not been clarified. We sought to determine whether selective disruption of FGF signaling affects arteriogenesis in the mouse model of hindlimb ischemia (HLI).
Methods: Two approaches were employed to disrupt FGF functions: conditional transgenic mice expressing a dominant-negative FGF-R1 (FGF-R1DN) construct capable of inactivation of all FGF signaling under control of Tie2 promoter in a tetracycline-regulatable manner, and a systemic expression of adenoviral vectors for soluble FGFR-IgFc chimeras (FGF Trap). Two FGF Traps were used to differentiate the contribution of specific FGFs: FGF-R1IIIc (FR1c) which binds FGF1, 2, 4, 5, 6, and FGF-R3IIIb (FR3b) which almost exclusively binds FGF1. HLI was induced by ligation of the right femoral artery either in FGF-R1DN mice or Ad-FGF Trap transduced mice.
Results: FGF-R1DN mice demonstrated toe/foot loss on the ischemic side following HLI, whereas no tissue loss was observed in control mice. This was accompanied by extensive apoptosis and concomitant reduction in tissue cGMP levels in FGF-R1DN mice. The post-ischemic flow recovery measured by laser Doppler imaging was markedly reduced in FGF-R1DN mice (R/L ratio, 0.33 ± 0.09 vs. 0.09 ± 0.06 at day 7, p<0.01). Quantitative Micro-CT analysis demonstrated a decreased number of <80μm arterioles at day 28 in the thigh and calf region of FGF-R1DN mice (n=6). FGF Trap mice also showed reduced flow recovery (R/L ratio, 0.52 ± 0.07 for control, 0.31 ± 0.02 for FR1c, and 0.40 ± 0.05 for FR3b at day 10, p<0.01). Micro-CT analysis for FGF Trap mice demonstrated a decrease in the development of <80μm arterioles in FR1c mice and a less significant decrease in FR3b mice (n=12).
Conclusion: Disruption of the FGF signaling in the endothelium in mice results in impairment of neovascularization and tissue protection in response to acute ischemia. The neovascularization defect is primarily limited to <80μm arterioles. The study shows the key role played by the FGF system in arteriogenesis, and suggests that multiple FGF ligands are involved.