Apelin promising therapy for diabetes patients with peripheral arterial disease

In diabetes patients, PAD is a major risk factor for lower-extremity amputation. However, previous clinical studies previous studies investigating therapeutic angiogenesis using the VEGF (vascular endothelial growth factor) have shown disappointing results in diabetes patients, evoking the need for novel therapeutic agents.

Under hypoxic conditions, the apelinergic system (APJ receptor/apelin) is highly upregulated and acts as an activator of angiogenesis. In nondiabetic models of ischemia, apelin treatment improves revascularization, however, its role in in angiogenesis in diabetic conditions has not been investigated well.

Stéphanie Robillard, Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada, and colleagues explored the impact of Pyr-apelin-13 in endothelial cell function and a diabetic mouse model of hindlimb ischemia.

For this purpose, diabetic and nondiabetic mice underwent femoral arteries to induce limb ischemia. Osmotic pumps delivering Pyr-apelin-13 were subcutaneously implanted in diabetic mice for 28 days. The measurement of blood flow reperfusion for 4 weeks post-surgery. Exercise willingness was evaluated with voluntary wheels.

Bovine aortic endothelial cells (BAECs) were exposed to normal (NG) or high glucose (HG) levels and hypoxia. Following either VEGF or Pyr-apelin-13 stimulation, the researchers performed cell migration, proliferation and tube formation assays.

The study led to the following findings:

• 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 signalling pathways under both NG or HG concentrations and hypoxia exposure.

In normoglycemic conditions, apelin proangiogenic actions are well documented. "Our results showed that, unlike VEGFR signalling pathways, the apelin/APJ pathways are not impacted by hyperglycemia, making the apelinergic system a potential target for angiogenic therapy," the researchers wrote.

Furthermore, they showed the Pyr-apelin-13's therapeutic effect in diabetic PAD, since its prolonged administration led to improved vascular density, blood flow reperfusion, and motor function in diabetic mice following hindlimb ischemia. However, it remains to be proven if apelin treatment can be an effective therapy for PAD and diabetes patients.

"The short half-life of apelin may represent a challenge for its use as a pharmacological treatment," the research team wrote. "Thus, to improve the long-term angiogenic response in diabetes, research must continue to develop more stable apelinergic agonists."

Reference:

Robillard, S., Trân, K., Lachance, M., Brazeau, T., Boisvert, E., Lizotte, F., Boudreault, P., Marsault, É., & Geraldes, P. (2023). Apelin prevents diabetes-induced poor collateral vessel formation and blood flow reperfusion in ischemic limb. Frontiers in Cardiovascular Medicine, 10, 1191891. https://doi.org/10.3389/fcvm.2023.1191891