Abstract
Therapeutic angiogenesis has been considered as a potential strategy for treating peripheral artery diseases including hind-limb ischemia (HLI); however, no effective drug-based treatment is currently available. Here we showed that intramuscular administration of salidroside, an active compound of Chinese herb Rhodiola, could robustly enhance blood perfusion recovery by promoting neovascularization in HLI mice. We revealed that salidroside promoted skeletal muscle cell migration and paracrine function through inhibiting the transcriptional level of prolyl-hydroxylase domain 3 (PHD3) without affecting PHD1 and PHD2. Paracrine signals from salidroside-treated skeletal muscle cells enhanced endothelial and smooth muscle cells migration, while inhibition of FGF2/FGF2R and PDGF-BB/PDGFR-β pathways abolished this effect, as well as neovascularization in HLI mice. Furthermore, we elucidated that salidroside inhibition on PHD3 might occur through estrogen receptor alpha (ERα). Together, our findings highlights the potential application of salidroside as a novel pharmalogical inhibitor of ERα/PHD3 axis for therapeutic angiogenesis in HLI diseases.
Highlights
Available[14,16,17,18,19,20,21,22]
When compared to the control group administered with phosphate-buffered saline (PBS), salidroside-treated hind-limb ischemia (HLI) mice displayed a significantly higher blood perfusion recovery at 21 days post-surgery. Consistent with these results, ischemic damage assessment showed that at 21 days post-surgery, HLI mice treated with salidroside scored 0–1, while those treated with PBS mice scored 2–4 (Fig. 1d)
We did not observe any obvious morphological changes in the liver, kidneys, spleen, and heart after a 2-month administration of salidroside (Supplementary Fig. 2). These results showed that intramuscular salidroside treatment could effectively increase the blood perfusion recovery in the ischemic hind limbs of HLI mice, most plausibly owing to the increase of the number of mature blood vessels in the ischemic hind limb
Summary
Available[14,16,17,18,19,20,21,22]. Rhodiola, a plant growing at high altitude and has been used since centuries in Chinese and Tibetan traditional medicine, has been known for its functions in enhancing adaptation to high-altitude and hypoxic condition, partly through the induction of EPO expression, as well as cell survival[23,24]. Recent studies have revealed that salidroside (2-[4-hydroxyphenyl]ethyl beta-d-glucopyranoside), which could be artificially synthesized, is the main compound responsible for the therapeutic effect of Rhodiola[25,26]. Whether or not salidroside exerts therapeutic angiogenesis effects in ischemic diseases has not been elucidated yet. Salidroside suppresses the expression level of PHD3 in skeletal muscle cells through estrogen receptor alpha (ERα). Specific inhibition of PHD3 by salidroside in skeletal muscle cells promoted their mobility, and concomitantly, their expression and secretion of angiogenic factors, which in turn enhanced cell–cell communication between skeletal muscle cells and endothelial and/or smooth muscle cells. We found that intramuscular salidroside administration inhibits PHD3 expressions in skeletal muscle cells, and led to effective neovascularization and blood perfusion recovery in a mouse model of HLI, indicating that salidroside might be a potential drug candidate for therapeutic angiogenesis in HLI
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