Abstract 2189: New Therapeutic Approach for Impaired Arteriogenesis in Diabetic Mouse Hindlimb Ischemia
Introduction: Diabetes mellitus (DM) has been identified as one of negative predictors of collateral vessel development. However, it remains unclear whether the poor arteriogenesis or angiogenesis is responsible for the impaired collateral blood flow (CBF). Also in DM, CBF is jeopardized by hypersensitivity to vasoconstriction by serotonin (5-HT) due to up-regulated 5-HT2A receptors in vascular smooth muscle cells.
Hypothesis: We assessed the hypothesis that the arteriogenesis is predominantly impaired in DM mouse hind limb ischemia model and the disorder is reversed by combined treatment of sustained release basic FGF and 5-HT2A blocker, sarpogrelate.
Methods: We induced hindlimb ischemia by excising the right femoral artery in streptozotocin induced DM mice. We used gelatin hydrogel microsphere as a sustained release carrier for basic FGF. Mice were supplemented with diet containing sarpogrelate (50 mg/kg/day). DM and control mice were randomly assigned into each experimental group (n=6–8) immediately after surgery and treated for 4 weeks. End point measurements at 4th wk were CBF by Laser Doppler perfusion image index, capillary density (angiogenesis; stained with mouse antimouse von Willebrand factor) and the number of mature vessels with a significant smooth muscle cell layer (arteriogenesis; stained with mouse anti-α-smooth muscle actin).
Results: CBF was significantly lower in DM mice than non-DM mice (0.46 ± 0.12 (SD) vs. 0.63 ± 0.08, p < 0.05). Although angiogenesis was comparable between the 2 groups (161 ± 17 vs. 160 ± 19 vessels/mm2), arteriogenesis was significantly lower in DM mice (6.6 ± 0.7 vs. 9.5 ± 2.8 vessels/mm2, p<0.05). The doses of sustained release basic FGF sufficient for arteriogenesis (≥ 45 vessels/mm2) and CBF (≥ 0.9) were 20 μg for non DM mice, and 50 μg for DM mice. Additional treatment with sarpogrelate decreased the dose of sustained release basic FGF to 20 μg to obtain the similar extent of CBF in DM mice.
Conclusions: Arteriogenesis and the recruitment of collateral vessels after the induction of hindlimb ischemia is significantly impaired in DM mice, and combined treatment of sustained-release basic FGF and sarpogrelate improves CBF presumably due to enhanced arteriogenesis and vasodilation of collateral vessels.