Secreted Frizzled-Related Protein 4 An Angiogenesis Inhibitor
Secreted Frizzled-Related Protein 4 An Angiogenesis Inhibitor
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DOI：
10.2353/ajpath.2010.090465
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发表时间：
2010-03-01
影响因子：
6
通讯作者：
Chatterjee, Suvro
中科院分区：
文献类型：
--
作者：
Muley, Ajit;Majumder, Syamantak;Chatterjee, Suvro
Wnt信号参与发育过程、细胞增殖和细胞迁移。分泌卷曲相关蛋白4 （sFRP4）已被证明是Wnt拮抗剂；然而，其对内皮细胞迁移和血管生成的影响尚未见报道。通过各种体外实验，我们发现sFRP4抑制内皮细胞迁移和芽和假足的发育，除了抑制增殖外，还破坏内皮环的稳定性。sFRP4通过拮抗典型的Wnt/ β -连环蛋白信号通路和Wnt/平面细胞极性通路干扰内皮细胞功能。此外，sFRP4阻断了血管内皮生长因子对内皮细胞的作用。sFRP4还通过增加细胞活性氧水平选择性诱导内皮细胞凋亡事件。体内实验表明，sFRP4治疗后血管功能减少。最重要的是，sFRP4通过干扰内皮细胞功能来限制小鼠的肿瘤生长。数据表明，SFRP4是一种有效的血管生成抑制剂，值得进一步研究作为一种治疗药物来控制血管生成相关病理。（美国病理学杂志，2010,176:1505-1516;DOI: 10.2353/ajpath.2010.090465）
Wnt signaling is involved in developmental processes, cell proliferation, and cell migration. Secreted frizzled-related protein 4 (sFRP4) has been demonstrated to be a Wnt antagonist; however, its effects on endothelial cell migration and angiogenesis have not yet been reported. Using various in vitro assays, we show that sFRP4 inhibits endothelial cell migration and the development of sprouts and pseudopodia as well as disrupts the stability of endothelial rings in addition to inhibiting proliferation. sFRP4 interfered with endothelial cell functions by antagonizing the canonical Wnt/beta-catenin signaling pathway and the Wnt/planar cell polarity pathway. Furthermore, sFRP4 blocked the effect of vascular endothelial growth factor on endothelial cells. sFRP4 also selectively induced apoptotic events in endothelial cells by increasing cellular levels of reactive oxygen species. In vivo assays demonstrated a reduction in vascularity after sFRP4 treatment. Most importantly, sFRP4 restricted tumor growth in mice by interfering with endothelial cell function. The data demonstrate SFRP4 to be a potent angiogenesis inhibitor that warrants further investigation as a therapeutic agent in the control of angiogenesis-associated pathology. (Am J Pathol 2010, 176:1505-1516; DOI: 10.2353/ajpath.2010.090465)