Macrophage induces angiogenesis via HIF signaling in denervated muscle following nerve injury

Skeletal muscle and blood vessels typically maintain independent homeostasis under normal physiological conditions. However, peripheral nerve injury often leads to skeletal muscle denervation, affecting the richly vascularized tissue. While previous studies have focused on the degradation processes in denervated skeletal muscle, the response of blood vessels to denervation remains poorly understood. This study utilized a denervated muscle model in Tie2Cre; R26RTd-tomato mice to investigate the changes in blood vessel behavior following denervation. Sciatic nerve ligation induced hypoxia and triggered angiogenesis during the acute phase after injury. In the chronic phase, quiescent endothelial cells were observed, with no active angiogenesis, despite the presence of a complex microvascular network in the long-term denervated muscle. Notably, macrophages accumulated in short-term denervated muscle, sensing hypoxia and activating the HIF-1 signaling pathway, which drives angiogenesis during the acute phase. Macrophage depletion suppressed the expression of pro-angiogenic factors and inhibited angiogenesis, underscoring their essential role in angiogenesis following muscle denervation. This study provides novel insights into the dynamic process of angiogenesis in denervated muscle and highlights the critical involvement of macrophages in this process.