Imaging the effect of receptor for advanced glycation endproducts on angiogenic response to hindlimb ischemia in diabetes

BACKGROUND Receptor for advanced glycation endproducts (RAGE) expression contributes to the impaired angiogenic response to limb ischemia in diabetes. The aim of this study was to detect the effect of increased expression of RAGE on the angiogenic response to limb ischemia in diabetes by targeting αvβ3 integrin with 99mTc-labeled Arg-Gly-Asp (RGD). METHODS Male wild-type (WT) C57BL/6 mice were either made diabetic or left as control for 2 months when they underwent femoral artery ligation. Four groups were studied at days 3 to 7 after ligation: WT without diabetes (NDM) (n = 14), WT with diabetes (DM) (n = 14), RAGE-/- NDM (n = 16), and RAGE-/- DM (n = 14). Mice were injected with 99mTc-HYNIC-RGD and imaged. Count ratios for ischemic/non-ischemic limbs were measured. Muscle was stained for RAGE, αvβ3, and lectins. RESULTS There was no difference in count ratio between RAGE-/- and WT NDM groups. Mean count ratio was lower for WT DM (1.38 ± 0.26) vs. WT NDM (1.91 ± 0.34) (P<0.001). Mean count ratio was lower for the RAGE-/- DM group than for RAGE-/- NDM group (1.75 ± 0.22 vs. 2.02 ± 0.29) (P<0.001) and higher than for the WT DM group (P<0.001). Immunohistopathology supported the scan findings. CONCLUSIONS In vivo imaging of αvβ3 integrin can detect the effect of RAGE on the angiogenic response to limb ischemia in diabetes.