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Resveratrol Promotes Angiogenesis in a FoxO1-Dependent Manner in Hind Limb Ischemia in Mice
Dongxiao Fan1,2, Chenshu Liu1,2, Zeling Guo3
1Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
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.
Insights
Resveratrol (RSV) improves critical limb ischemia (CLI) by promoting angiogenesis, a process dependent on the protein FoxO1. This study reveals metabolic pathways linked to RSV
Area of Science:
- Vascular Biology
- Molecular Medicine
- Metabolomics
Background:
- Critical limb ischemia (CLI) is a severe manifestation of peripheral artery disease (PAD) with limited therapeutic options.
- Therapeutic angiogenesis aims to improve collateral circulation in CLI, but drug development is challenging.
- Resveratrol (RSV), a plant-derived polyphenol, exhibits various beneficial properties, but its role in CLI is not well understood.
Purpose of the Study:
- To investigate the therapeutic potential of Resveratrol (RSV) in treating critical limb ischemia (CLI).
- To elucidate the molecular mechanisms underlying RSV's effects on angiogenesis in CLI.
- To identify metabolic pathways influenced by RSV intervention in ischemic conditions.
Main Methods:
- Oral administration of RSV to a mouse model of hind limb ischemia.
- In vitro studies using human umbilical vein endothelial cells (HUVECs) to assess angiogenesis and FoxO1 phosphorylation.
- Genetic manipulation of FoxO1 in HUVECs to confirm its role in RSV's effects.
- Metabolomic analysis to identify altered metabolic pathways.
Main Results:
- RSV treatment significantly improved hind limb ischemia in mice.
- RSV enhanced angiogenesis in HUVECs by increasing phosphorylated Forkhead box class-O1 (FoxO1) and promoting its cytoplasmic re-localization.
- The pro-angiogenic effects of RSV were confirmed to be FoxO1-dependent.
- Metabolomics revealed correlations between RSV's beneficial effects and pathways including pyrimidine metabolism, purine metabolism, and alanine, aspartate, and glutamate metabolism.
Conclusions:
- Resveratrol demonstrates therapeutic potential for critical limb ischemia (CLI) by promoting angiogenesis.
- RSV exerts its pro-angiogenic effects through a FoxO1-dependent mechanism.
- Specific metabolic pathways are significantly altered by RSV, contributing to its protective effects in ischemic muscle, offering novel therapeutic avenues for CLI.
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