Canonical Wnt Signaling Promotes Neovascularization Through Determination of Endothelial Progenitor Cell Fate via Metabolic Profile Regulation
Canonical Wnt Signaling Promotes Neovascularization Through Determination of Endothelial Progenitor Cell Fate via Metabolic Profile Regulation
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DOI：
10.1002/stem.3049
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发表时间：
2019-07-22
期刊：
影响因子：
5.2
通讯作者：
Ma, Jian-Xing
中科院分区：
文献类型：
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作者：
Shao, Yan;Chen, Jianglei;Ma, Jian-Xing
内皮祖细胞 (EPC) 有助于血管形成。经典Wnt信号在生理和病理性血管生成以及EPC命运调控中发挥着重要作用。然而，Wnt信号传导在新生血管形成（NV）中调节EPC命运的机制尚未明确。在这里，我们发现极低密度脂蛋白受体敲除（Vldlr（-/-））小鼠（一种由 Wnt 信号过度激活诱导的眼部 NV 模型）的骨髓、血液和视网膜中的 EPC 数量增加，线粒体膜电位升高，表明循环中 EPC 的线粒体功能更高。与 WT EPC 相比，Vldlr(-/-) 小鼠分离的 EPC 显示出过度激活的 Wnt 信号传导，与线粒体功能、质量和 DNA 拷贝数增加相关。我们的结果还表明，Wnt 信号传导上调线粒体生物发生和功能，同时抑制 EPC 中的糖酵解，这进一步降低了 EPC 的干性，并促进 EPC 进入更活跃的分化状态，这可能有助于病理性血管形成。 Fenofibric Acid 是非诺贝特的活性代谢物，可抑制 EPC 中的 Wnt 信号传导和线粒体功能，并减少 Vldlr(-/-) 小鼠中的 EPC 数量。它还减少了 Vldlr(-/-) EPC 中线粒体的生物发生和活性氧的产生，这可能是其对糖尿病视网膜病变的治疗作用的原因。这些发现表明 Wnt 信号通过代谢调节 EPC 命运，表明 EPC 代谢谱作为新生血管疾病的预测因子和治疗靶点的潜在应用。
Endothelial progenitor cells (EPCs) contribute to blood vessel formation. Canonical Wnt signaling plays an important role in physiological and pathological angiogenesis and EPC fate regulation. However, the mechanism for Wnt signaling to regulate EPC fate in neovascularization (NV) has not been clearly defined. Here, we showed that very low-density lipoprotein receptor knockout (Vldlr(-/-)) mice, a model of ocular NV induced by Wnt signaling overactivation, have increased EPC numbers in the bone marrow, blood, and retina, as well as an elevated mitochondrial membrane potential indicating higher mitochondrial function of EPCs in the circulation. Isolated EPCs from Vldlr(-/-) mice showed overactivated Wnt signaling, correlating with increased mitochondrial function, mass, and DNA copy numbers, compared with WT EPCs. Our results also demonstrated that Wnt signaling upregulated mitochondrial biogenesis and function, while inhibiting glycolysis in EPCs, which further decreased EPC stemness and promoted EPCs to a more active state toward differentiation, which may contribute to pathologic vascular formation. Fenofibric acid, an active metabolite of fenofibrate, inhibited Wnt signaling and mitochondrial function in EPCs and decreased EPC numbers in Vldlr(-/-)mice. It also decreased mitochondrial biogenesis and reactive oxygen species production in Vldlr(-/-) EPCs, which may be responsible for its therapeutic effect on diabetic retinopathy. These findings demonstrated that Wnt signaling regulates EPC fate through metabolism, suggesting potential application of the EPC metabolic profile as predictor and therapeutic target for neovascular diseases.