Abstract 5826: MicroSPECT-CT Imaging Demonstrates Impairment of Matrix Metalloproteinases Activation in Ischemic Peripheral Angiogenesis in Type-1 Diabetes Associated with Glycation
We previously demonstrated an impairment of ischemic peripheral angiogenesis (IPA) in a murine model of hindlimb ischemia using a radiolabeled RGD peptide targeted at alpha-v integrin in type-1 diabetes mellitus (DM) in association with advanced glycation endproducts (AGE). Glycation of the extracellular matrix (ECM) in DM inhibits ECM degradation by matrix metalloproteinases (MMPs), and impairs IPA. We hypothesized that targeted microSPECT-CT imaging of MMP activation with 99mTc-labeled peptidomimetic (RP805; Lantheus, USA) would demonstrate impaired MMP activation during IPA in DM in association with AGE accumulation. Right femoral artery was surgically ligated on C57BL/6 male non-DM mice (n= 12) and DM mice (n= 17) 4–6 wks after STZ treatment (40 mg/kg i.p. for 5 days). DM mice demonstrated glycosuria and fasting glycemia (>200 mg/dL). RP805 (1.6± 0.5mCi) was injected and microSPECT-CT imaging performed 60 min later in mice 1 week (non-DM: n= 5; DM: n= 9) and 2 weeks (non-DM: n= 7; DM: n= 8) post-ligation. Blood was collected in additional non-DM (n= 4) and DM (n= 4) mice for measurement of HbA1c, an index of AGE accumulation. MicroSPECT-CT images were analyzed for RP805 activity within hindlimb distal to ligation, and ischemic-to-nonischemic (I/N) activity ratios calculated. DM mice demonstrated ~3-fold increase in glucose levels, and ~2.7-fold increase in AGE. Quantitative RP805 imaging demonstrated an impairment of MMP activation (~47%, P< 0.05) in DM at 1 week post-ligation, which normalized at 2 weeks. RP805 microSPECT-CT imaging provides a novel non-invasive approach for evaluation of impaired MMP activation during IPA in DM, and was associated with AGE accumulation.