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A Modified Surgical Model of Hind Limb Ischemia in ApoE-/- Mice using a Miniature Incision
Published on: May 13, 2021
Apelin prevents diabetes-induced poor collateral vessel formation and blood flow reperfusion in ischemic limb
Stéphanie Robillard1, Kien Trân2, Marie-Sophie Lachance1
1Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
Introduction:
Peripheral arterial disease (PAD) is a major risk factor for lower-extremity amputation in diabetic patients. Unfortunately, previous clinical studies investigating therapeutic angiogenesis using the vascular endothelial growth factor (VEGF) have shown disappointing results in diabetic patients, which evokes the necessity for novel therapeutic agents. The apelinergic system (APJ receptor/apelin) is highly upregulated under hypoxic condition and acts as an activator of angiogenesis. Apelin treatment improves revascularization in nondiabetic models of ischemia, however, its role on angiogenesis in diabetic conditions remains poorly investigated. 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 limb ischemia. Diabetic mice were 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 with voluntary wheels. In vitro, bovine aortic endothelial cells (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 And Discussion:
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. Our results identified the apelinergic system as a potential therapeutic target for angiogenic therapy in diabetic patients with PAD.
Insights
Pyr-apelin-13 improved blood flow and limb function in diabetic mice with peripheral arterial disease. This peptide’s proangiogenic effects were maintained in high glucose and hypoxic conditions, unlike VEGF.
Area of Science:
- Vascular Biology and Regenerative Medicine
- Diabetic Complications
- Angiogenesis Therapeutics
Background:
- Peripheral arterial disease (PAD) significantly increases amputation risk in diabetic patients.
- Vascular endothelial growth factor (VEGF) therapy has shown limited efficacy in diabetic angiogenesis.
- The apelinergic system's role in diabetic angiogenesis remains underexplored.
Purpose of the Study:
- To investigate the therapeutic potential of Pyr-apelin-13 in promoting angiogenesis in diabetic conditions.
- To evaluate the impact of Pyr-apelin-13 on endothelial cell function under high glucose and hypoxic stress.
- To assess Pyr-apelin-13 efficacy in a diabetic mouse model of hindlimb ischemia.
Main Methods:
- Diabetic and nondiabetic mice underwent hindlimb ischemia surgery.
- Pyr-apelin-13 was administered via osmotic pumps to diabetic mice for 28 days.
- In vitro studies assessed endothelial cell migration, proliferation, and tube formation under varying glucose and oxygen levels, with VEGF or Pyr-apelin-13 stimulation.
Main Results:
- Pyr-apelin-13 treatment significantly improved blood flow, functional recovery, and vascular density in diabetic mice post-ischemia.
- Unlike VEGF, Pyr-apelin-13 retained its proangiogenic effects on endothelial cells under high glucose and hypoxic conditions.
- Pyr-apelin-13 mediated its effects via Akt/AMPK/eNOS and RhoA/ROCK signaling pathways.
Conclusions:
- The apelinergic system, specifically Pyr-apelin-13, represents a promising therapeutic target for angiogenic therapy in diabetic PAD patients.
- Pyr-apelin-13 demonstrates efficacy in overcoming the impaired angiogenesis associated with diabetes.
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