Candesartan protects against unilateral peripheral limb ischemia in type-2 diabetic rats: Possible contribution of PI3K-Akt-eNOS-VEGF angiogenic signaling pathway.

ABSTRACT

Type-2 diabetes (T2DM) is known to be highly associated with increased risk for vascular complications including peripheral arterial diseases (PAD). Critical limb ischemia (CLI) is the most advanced stage of PAD. Current therapeutic options for diabetic patients experiencing vascular complications are limited to surgical revascularization with no effective pharmacotherapy available for clinical settings. This study is dedicated to evaluate the angiogenic potential of candesartan an angiotensin-II receptor blocker in an experimental model of vascular complications associating T2DM. T2DM was induced in rats through feeding with high fat diet for 6 weeks, followed by injection with streptozotocin (STZ, 30 mg/kg; i.p). After establishment of T2DM, unilateral CLI was induced through the ligation and excision of superficial femoral artery. Candesartan treatment (10 or 30 mg/kg; orally) was initiated one day post CLI and thereafter once daily for up to 14 days. T2DM rats that underwent CLI demonstrated impaired angiogenic signaling, increased inflammation and apoptosis in gastrocnemius muscle (GC). Candesartan reversed ischemic insult in T2DM rats subjected to unilateral CLI and induced reparative angiogenesis that was evident by increase in p-PI3K/PI3K, p-Akt/Akt, p-eNOS/eNOS, p-VEGFR2/VEGFR2 ratios, and VEGF levels. Candesartan treatment also increased levels of HO-1; while decreased caspase-3 apoptotic marker and levels of inflammatory markers; NF-κB and TNF-α, all of which were accompanied by preserved histological manifestations of GC muscles. Candesartan was able to combat limb ischemia under diabetic conditions which could pave the way for its therapeutic utility for diabetic patients experiencing vascular complications in clinical setting.