Novel RAGE antagonist, FPS‐ZM1, reverses mesenteric arteriolar remodeling in type 2 diabetic db/db mice.

Type II diabetes (T2D) is a major risk factor for cardiovascular diseases. Recently, our laboratory established a differential effect of T2D on vascular remodeling that was dependent upon vessel size and location. In addition, our preliminary data showed an increase in circulating levels of advanced glycation end products (AGE) in T2D mice. Activation of AGE receptors (RAGE) was shown to be associated with vascular dysfunction and vascular smooth muscle proliferation, which may result in vascular remodeling. In the present study, we hypothesized that pharmacological RAGE blockade using a novel antagonist would reverse microvascular remodeling observed in T2D. Using a pressure myograph system, passive vascular mechanics were assessed in aortae and mesenteric arterioles (MA) isolated from 16 week-old lean control mice (Db/db), obese T2D mice (db/db) and T2D mice (db/db+FPS) treated with RAGE antagonist (FPS-ZM1, 1mg/Kg/day ip, 28 days). Body weight (BW) and fasting blood glucose (BG) were significantly increased in diabetic db/db compared to control Db/db mice (BW: 29.8±0.5 in Db/db vs. 47.3± 1.5 g db/db, p<0.05 and BG: 185 Db/db ± 13 vs 687 ± 20 mg/dL in db/db, p<0.05). FPS-ZM-1 treatment did not affect BW (46.3±1.5g) nor BG (679±17 mg/dL) in T2D mice. In aorta, neither diabetes nor RAGE antagonism in diabetic mice affected the macrovascular mechanical properties. In contrast, MAs isolated from T2D mice exhibited a significant increase in internal diameter (158±2 in Db/db vs. 208±13 μm in db/db at 100mmHg, p<0.05), external diameter (180±3 in Db/db vs. 233±14 μm in db/db at 100mmHg, p<0.05) and cross-sectional area (CSA) (6066±597 in Db/db vs. 8753±881 μm2 in db/db at 100mmHg, p<0.05). RAGE antagonism in T2D significantly reduced MAs internal diameter (178±5 in db/db+FPS vs. 208±13 μm in db/db at 100mmHg, p<0.05), external diameter (200±5 in db/db+FPS vs. 233±14 μm in db/db at 100mmHg, p<0.05) and CSA (6453±400 in db/db+FPS vs. 8753±881 μm2 in db/db at 100mmHg, p<0.05). Together, our data showed a variation in macrovascular vs. microvascular remodeling in T2D as we have previously shown. Furthermore, our data suggest that AGE/RAGE signaling contributes to the microvascular remodeling observed in T2D and that RAGE blockade using a novel antagonist may present a potential therapeutic target to reduce or reverse diabetes-mediated vascular complications.