Abstract
Critical limb ischemia (CLI) is a severe form of peripheral artery diseases (PAD) and seriously endangers the health of people. Therapeutic angiogenesis represents an important treatment strategy for CLI; various methods have been applied to enhance collateral circulation. However, the current development drug therapy to promote angiogenesis is limited. Resveratrol (RSV), a polyphenol compound extracted from plants, has various properties such as anti-oxidative, anti-inflammatory and anti-cancer effects. Whether RSV exerts protective effects on CLI remains elusive. In the current study, we demonstrated that oral intake of RSV significantly improved hind limb ischemia in mice, and increased the expression of phosphorylated Forkhead box class-O1 (FoxO1). RSV treatment in human umbilical vein endothelial cells (HUVECs) could increase the phosphorylation of FoxO1 and its cytoplasmic re-localization to promote angiogenesis. Then we manipulated FoxO1 in HUVECs to further verify that the effect of RSV on angiogenesis is in a FoxO1-dependent manner. Furthermore, we performed metabolomics to screen the metabolic pathways altered upon RSV intervention. We found that the pathways of pyrimidine metabolism, purine metabolism, as well as alanine, aspartate and glutamate metabolism, were highly correlated with the beneficial effects of RSV on the ischemic muscle. This study provides a novel direction for the medical therapy to CLI.
Highlights
We explored the protective effects of RSV on hind limb ischemia mice by observing blood flow recovery after intervention
At day 4 after surgery, the blood flow perfusion of ischemic hind limbs in the ischemia + RSV group showed a full recovery to the presurgery level, whereas the ischemia group showed a recovery of 25.62% to the pre-surgery level
After 8 h RSV treatment in two different concentrations, the length of tube was longer than that in the DMSO group under hypoxia condition (Figure 2H,I). These results indicated that RSV increased phosphorylated Forkhead box class-O1 (FoxO1) and promoted angiogenesis in human umbilical vein endothelial cells (HUVECs) in an ischemic condition
Summary
Critical limb ischemia (CLI) is the most severe form of PAD. It has been reported that 20% of patients with chronic CLI would die within the first year of symptom onset [3]. Ischemia and foot infection are three major factors contributing to threatened lower limb (TLL), and ischemia is the dominant risk for amputation [4]. For the treatment of PAD, revascularization is an effective therapy. Pharmacotherapy is still widely used with a considerable treatment efficiency. Contemporary drugs for PAD are mainly used for treating atherosclerosis to alleviate symptoms and to reduce cardiovascular events; the medicine for severe forms of PAD such as CLI is scarce
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