Salidroside analogue C-30 promotes neovascularization in diabetic hindlimb ischemic mice by inducing macrophage M2 polarization

Hindlimb ischemia (HLI) is a disease caused by the obstruction of blood vessels, and is a major complication of diabetes. Therapeutic angiogenesis, which aims to promote angiogenesis and blood perfusion recovery, is a potential therapeutic strategy for HLI. However, hyperglycemia systematically impairs intrinsic angiogenesis potential, including macrophage polarization from M1 to M2, thereby impeding efficient therapeutic angiogenesis. Salidroside-derived glycoside analogue C-30 (C₂₀H₂₄O₇), which was synthesized in our previous study, has markedly enhanced the therapeutic angiogenesis potential in diabetic HLI mice; however, the underlying molecular mechanism remains unknown, and whether it could induce macrophage M2 polarization under hyperglycemia remains unclear. Herein, we revealed that C-30 could significantly promote macrophage M2 polarization under hyperglycemia. Through transcriptomic analysis and validation at cellular level, we revealed that C-30 could suppress hyperglycemia-induced NF-κB signaling pathway activation in macrophages, thereby enhancing oxidative phosphorylation, and eventually, M2 polarization. This in turn facilitates macrophage-blood vessel-forming cells crosstalk and augments angiogenic potential under hyperglycemia. Importantly, intramuscular administration of the NF-κB activator CU-T12-9 abolished C-30-mediated upregulation of macrophage polarization and homeostasis, and eventually, angiogenesis in diabetic HLI mice. Together, these findings clearly show that C-30 could enhance neovascularization and functional blood vessel formation by inducing macrophage M2 polarization in diabetic hindlimb ischemia mice. This study highlights the potential of intramuscularly injected salidroside-derived glycoside analogue in treating diabetic HLI by targeting macrophage M2 polarization.