Administration of Slow-Release Synthetic Prostacyclin Agonist Promoted Angiogenesis and Skeletal Muscle Regeneration for Limb Ischemia

Takaya Nakagawa,Shigeru Miyagawa,Takashi Shibuya,Yoshiki Sakai,Akima Harada,Kenichi Watanabe,Yoshiki Sawa

doi:10.1016/j.omtm.2020.05.022

Takaya Nakagawa, Shigeru Miyagawa + Show 5 more

Open Access

https://doi.org/10.1016/j.omtm.2020.05.022

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Abstract

Gene or cell therapy is currently not fully efficacious for arteriosclerosis obliterans (ASO). In this study, we determined whether YS-1402, a slow-release synthetic prostacyclin agonist, promoted neovascularization and skeletal muscle regeneration in a mouse model of critical limb ischemia (CLI). We ligated the femoral artery and its branches to obtain the CLI mouse model, administered saline (S group) or YS-1402 (YS group) to the thigh adductor 1 week after femoral artery occlusion, and evaluated tissue blood flow after surgery. After treatment, the leg muscle was obtained for histological, gene expression, and protein analyses to assess angiogenesis and skeletal muscle regeneration. Tissue blood flow improved in the YS group compared with that in the S group, and the number of CD31+/α-smooth muscle actin (αSMA)+ arterioles increased in the YS group. Prostacyclin receptor (IPR), stromal cell-derived factor-1, hepatocyte growth factor, and neural cell adhesion molecule expression levels were higher in the YS than in the S group. Skeletal muscle regeneration was detected based on PAX7- and Ki-67-positive satellite cells in the YS group. Myogenin and MyoD expression was higher in the YS than in the S group. Therefore, YS-1402 promoted functional angiogenesis and skeletal muscle regeneration in the CLI mouse model, suggesting a new therapy for ASO.

Highlights

Critical limb ischemia (CLI) is a peripheral artery disease that results in severe blockage of the arteries of the lower extremities, has a high mortality and limb amputation rates, and usually has a poor prognosis.[1,2,3,4] Currently, oral medications, bypass surgeries, and endovascular treatments are used for treatment
Increase in Capillary and Arteriolar Density The YS group demonstrated a significant increase in the number of CD31+/a-smooth muscle actin+ arterioles compared to the S group (458 ± 32.2 and 178 ± 30.6/mm[2], respectively; p < 0.01) (Figure 3A)
The gastrocnemius muscle was obtained to analyze the expression of angiogenesis-related factors (VEGF, hepatocyte growth factor (HGF), stromal cell-derived factor-1 (SDF-1)), angiogenesis maturation-related factors, bone marrow mesenchymal stem cell induction factor (SDF-1), IPRs, and neural cell adhesion molecule (NCAM) using real-time polymerase chain reaction (PCR)

Summary

Introduction

Critical limb ischemia (CLI) is a peripheral artery disease that results in severe blockage of the arteries of the lower extremities, has a high mortality and limb amputation rates, and usually has a poor prognosis.[1,2,3,4] Currently, oral medications, bypass surgeries, and endovascular treatments are used for treatment. There is no indication for revascularization in approximately 25%‒40% of CLI patients, and sufficient treatment has not been established.[2] development of a new treatment method is required. Revascularization therapy for peripheral vascular diseases includes gene therapy (such as vascular endothelial growth factor [VEGF]), autologous stem cell therapy (such as autologous bone marrow hepatocyte transplantation), and cytokine therapy (such as granulocyte colony-stimulating factor).[5,6,7,8,9] none of these therapies has been established to be safe and efficient for treatment.[10,11,12]

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