Elevating VEGF-A and PDGF-BB secretion by salidroside enhances neoangiogenesis in diabetic hind-limb ischemia

Hind-limb ischemia (HLI) is one of the major complication of diabetic patients. Angiogenesis potential in diabetic patients is severely disrupted, and the mechanism underlying it has not been fully elucidated, making it an obstacle for developing an efficient therapeutic angiogenesis strategy. Skeletal muscle cells, through their paracrine function, had been known to be critical for neoangiogenesis. Here we found that hyperglycemia upregulates the expression of skeletal muscle cells prolyl hydroxylase domain 3 (PHD3), which resulted in the decrease of the secretion of angiogenic factors, especially VEGF-A and PDGF-BB. We showed that treatment with salidroside, a small molecule drug, significantly suppresses PHD3 expression and increases VEGF-A and PDGF-BB secretion from skeletal muscle cells, which in turn enhances the proliferation and migration potentials of endothelial and smooth muscle cells. Finally, we demonstrated that intramuscular injection of salidroside into the ischemic hind limbs of diabetic HLI model mice could efficiently induce neoangiogenesis and blood perfusion recovery. Thus, our novel findings not only reveal the effects of hyperglycemia on the angiogenesis potential of skeletal muscle cells and the mechanism underlying it, but also provides a novel finding suggesting that salidroside might be a potential small molecule drug for diabetic HLI.