Fig. 8.

SFN enhances blood perfusion and angiogenesis in db/db mice with HLI.db/db mice (FVB background) were pretreated with SFN for 1 week, followed by HLI surgery and continual SFN treatment for additional 4 weeks. (A) The time-course of blood perfusion before (BEF) and after HLI surgery was monitored by a Pericam Perfusion Speckle Imager, and the data was quantified by Image J and expressed as the percentage of the perfusion relative to the collateral nonischemic limb. (B) Transverse sections of ischemic gastrocnemius and soleus muscle were stained with Alexa Fluor® 594 conjugated isolectin to enumerate isolectin-stained cell number as a proxy of capillary density. Capillary density was expressed as isolectin⁺ capillaries per muscle fiber. (C) At day 7 after HLI surgery, peripheral blood was collected to evaluate the percentage of EPCs (CD34⁺/VEGFR2⁺) in circulation by a flow cytometry. n = 6 mice per group. Data shown in graphs represent the means ± SD. *P < 0.05 vs Vehicle group. (D) Schematic illustration of the protective effects of Nrf2 on EPCs under diabetic conditions. Diabetes decreases expression of Nrf2 in EPCs and induces mitochondrial fission and dysfunction, resulting in reactive oxygen species (ROS) overproduction and cell death, ultimately leading to EPC dysfunction. Upregulation of Nrf2 by transgene or supplementation of SFN can rescue diabetes-induced inhibition of Nrf2 transcriptional activity, resulting in upregulation of IDH2 transcription, which inhibits mitochondrial fission, rectifies mitochondrial function, and decreases ROS production and cell death, ultimately rescues EPC dysfunction. ARE, antioxidant responsive element.