Myonectin stimulates endothelial angiogenic activity in vitro and in vivo

Endurance exercise is known to reduce the risk of cardiovascular disease. Myonectin, a myokine, is increased by endurance exercise and affects remote organs such as the heart. However, the role of myonectin in the blood vessels is unknown. In this study, we investigated the role of myonectin in angiogenesis. Human umbilical vein endothelial cells (HUVECs) were treated with recombinant myonectin to assess tube formation, proliferation, and migration. An in vivo Matrigel plug assay was performed by transplanting Matrigel containing myonectin into myonectin-knockout (Myo-KO) mice, and angiogenic response was evaluated. Mouse models of hindlimb ischemia were developed by ligating and removing the femoral arteries of wild-type (WT), Myo-KO, and myonectin-overexpressing transgenic (Myo-TG) mice, and blood flow was evaluated over time by laser Doppler imaging. In vitro, treatment with myonectin increased the differentiation of HUVECs into vascular-like structures. Myonectin significantly stimulated HUVEC migration, as assessed using a modified Boyden chamber assay. Treatment with myonectin also increased HUVEC proliferation, as assessed by the MTS assay. In the Matrigel plug assay, plugs containing myonectin displayed a significantly higher-degree of endothelial cell infiltration than plugs containing vehicle. Angiogenic repair of ischemic hindlimbs was impaired in Myo-KO mice compared to that in WT mice. However, Myo-TG mice had significantly increased limb perfusion after ischemic surgery compared to that in WT mice. This study showed that myonectin acts directly on vascular endothelial cells and promotes angiogenesis. Treatment aimed at increasing myonectin production may be useful in the treatment of cardiovascular diseases with vascular dysfunction.