Abstract
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.
Highlights
Diabetes mellitus is a chronic metabolic disorder that is characterized by hyperglycemia, which could result in serious damages to the heart, eyes, kidneys, nerves and blood vessels [1, 2]
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 vascular endothelial growth factor (VEGF-A) and platelet-derived growth factor (PDGF)-BB
Given that PHD3 increases the degradation of hypoxia-inducible factor1α (HIF-1α) protein, a key factor of angiogenesis that regulates multiple angiogenic factors including vascular endothelial growth factor (VEGF)-A and platelet derived growth factorBB (PDGF-BB) [16, 22, 23], we examined whether the suppressive effect of salidroside on PHD3 expression was able to induce HIF-1α protein accumulation
Summary
Diabetes mellitus is a chronic metabolic disorder that is characterized by hyperglycemia, which could result in serious damages to the heart, eyes, kidneys, nerves and blood vessels [1, 2]. The prognosis of diabetic HLI patients is significantly worse than the non-diabetic ones: amputation risk of diabetic patients with HLI is 5 times higher, while the mortality rate is more than 3 times higher [6]. Conventional treatments, such as surgical approach using cathether- or stentbased revascularization is not effective for diabetic HLI patients, as they usually have large wound surface and high recurrence rate [7]. The detail mechanism of the impaired angiogenesis potential induces by hyperglycemia remains unknown, rendering the development of potential, effective therapeutic strategy
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