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• W4320039998 abstract "Abstract BACKGROUND Peripheral artery disease (PAD) is a major risk factor for lower-extremity amputation in diabetic patients caused by an insufficient angiogenic response. Unfortunately, therapeutic angiogenesis using growth factors, such as the vascular endothelial growth factor (VEGF), are ineffective in diabetic conditions due to diabetes-induced growth factor resistance. The apelinergic system (APJ receptor/apelin) is highly upregulated under hypoxic condition and acts as an activator of angiogenesis. Apelin treatment has been shown to improve revascularization in nondiabetic models of ischemia, however, its role on angiogenesis in diabetic conditions remains poorly investigated. Thus, this study explored the impact of Pyr-apelin-13 in endothelial cell function and diabetic mouse model of hindlimb ischemia. METHODS Nondiabetic and diabetic mice underwent femoral artery ligation to induce lower limb ischemia. A group of diabetic mice was implanted subcutaneously with osmotic pumps delivering Pyr-apelin-13 for 28 days. Blood flow reperfusion was measured for 4 weeks post-surgery and exercise willingness was assessed in individual cages with voluntary wheels. In vitro , BAECs were exposed to normal (NG) or high glucose (HG) levels and hypoxia. Cell migration, proliferation and tube formation assays were performed following either VEGF or Pyr-apelin-13 stimulation. RESULTS Following limb ischemia, blood flow reperfusion, functional recovery of the limb and vascular density were improved in diabetic mice receiving Pyr-apelin-13 compared to untreated diabetic mice. In cultured BAECs, exposure to HG concentrations and hypoxia reduced VEGF proangiogenic actions, whereas apelin proangiogenic effects remained unaltered. Pyr-apelin-13 induced its proangiogenic actions through Akt/AMPK/eNOS and RhoA/ROCK signaling pathways under both NG or HG concentrations and hypoxia exposure. CONCLUSIONS Pyr-apelin-13 promoted endothelial cell function and angiogenesis in the ischemic limb despite diabetes and HG level exposure. Therefore, our results identified the apelinergic system as a potential therapeutic target for angiogenic therapy in diabetic patients with PAD. Highlights Sustained delivery of Pyr-apelin-13 improves blood flow reperfusion, functional recovery of the hindlimb and capillary density in diabetic mice following ischemia. Unlike VEGF, signaling pathways and proangiogenic actions induced by apelin/APJ stimulation are not impaired by high glucose exposure. Despite the presence of tissue ischemia, diabetes reduces the expression of apelin and APJ in the ischemic adductor muscle, an effect overcome by apelin administration." @default.
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• W4320039998 date "2023-02-11" @default.
• W4320039998 modified "2023-09-26" @default.
• W4320039998 title "Apelin improves angiogenesis and blood flow reperfusion following lower limb ischemia in diabetic mice" @default.
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• W4320039998 doi "https://doi.org/10.1101/2023.02.08.527688" @default.
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