Abstract 5315: Receptors for Advanced Glycation Endproducts Cause Decreased Collateral Vessel Formation in the Face of Uncontrolled Diabetes
Introduction: Diabetes Mellitus (DM) is associated with the development of poor collateral vasculature. The precise cellular and molecular processes are not well understood, but monocytes (MO) play a critical role. Chronic DM leads to the formation of advanced glycation endproducts (AGEs) which alter molecular functions through the Receptor for Advanced Glycation Endproducts (RAGE). The major goal of this study was to explore the contribution of RAGE to impaired collateral growth in the setting of DM, specifically when absent from MO.
Hypothesis: Decreased RAGE on MO leads to improved collateral vasculature in the setting of hyperglycemia.
Methods: Four groups of mice on a C57/Bl6 background were created: Wild type (WT), WT + DM, RAGE Knockout (RAGE KO), RAGE KO + DM. Streptozocin was given intraperitoneally to induce DM. After 4 weeks of DM, the left femoral artery was ligated for a hind limb ischemia model. Laser Doppler Perfusion Imaging (LDPI) was used for qualitative evaluation of collateral vessel development. Alpha-actin smooth muscle staining was used for quantitative anatomic evaluation of neovascularization. Spontaneous running duration was employed as a functional endpoint. Adoptive transfer was used to assess MO involvement. WT + DM mice were injected with RAGE KO MO and RAGE KO + DM mice were injected with WT MO on post-op days 0,2,5,7. LDPI was performed on post-op days 1 and 8
Results: WT + DM mice had the lowest level of blood flow recovery of all three groups, with a significant difference when compared to RAGE KO + DM (34% +/− 6.3%, 80.8 %+/− 12%; p< 0.001). These significant differences between WT + DM and RAGE KO + DM mice were also present when assessing data obtained from the running wheels (463m +/− 34m, 40, 938m +/− 342m; p<0.001) and histology when assessing the number of new vessels(v) (−9.6v +/− 38.2v, 409.1v +/− 86.9v; p< 0.05). Perfusion ratios were increased in WT + DM mice treated with RAGE KO MO by LDPI on post-op day 8 when compared to perfusion ratios seen in WT + DM mice without RAGE KO MO injection when normalized to the perfusion ratios obtained on post-op day1 (2.3% +/− 0.6% v. 1.04% +/− 0.09%; p< 0.05).
Conclusions: RAGE on MO appears to play a significant role in the hindrance of collateral vessel development in the face of hyperglycemia.