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首页> 外文期刊>The journal of clinical investigation >The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells
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The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells

机译：WNT拮抗剂Dickkopf2促进啮齿动物和人内皮细胞的血管生成

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Neovessel formation is a complex process governed by the orchestrated action of multiple factors that regulate EC specification and dynamics within a growing vascular tree. These factors have been widely exploited to develop therapies for angiogenesis-related diseases such as diabetic retinopathy and tumor growth and metastasis. WNT signaling has been implicated in the regulation and development of the vascular system, but the detailed mechanism of this process remains unclear. Here, we report that Dickkopf1 (DKK1) and Dickkopf2 (DKK2), originally known as WNT antagonists, play opposite functional roles in regulating angiogenesis. DKK2 induced during EC morphogenesis promoted angiogenesis in cultured human endothelial cells and in in vivo assays using mice. Its structural homolog, DKK1, suppressed angiogenesis and was repressed upon induction of morphogenesis. Importantly, local injection of DKK2 protein significantly improved tissue repair, with enhanced neovascularization in animal models of both hind limb ischemia and myocardial infarction. We further showed that DKK2 stimulated filopodial dynamics and angiogenic sprouting of ECs via a signaling cascade involving LRP6-mediated APC/Asef2/Cdc42 activation. Thus, our findings demonstrate the distinct functions of DKK1 and DKK2 in controlling angiogenesis and suggest that DKK2 may be a viable therapeutic target in the treatment of ischemic vascular diseases.
机译：新血管形成是一个复杂的过程，受多种因素共同作用的调节，这些因素调节着生长中的血管树中的EC规格和动力学。这些因素已被广泛开发用于开发与血管生成有关的疾病的疗法，例如糖尿病性视网膜病以及肿瘤的生长和转移。 WNT信号传导已牵涉到血管系统的调节和发展，但此过程的详细机制仍不清楚。在这里，我们报告Dickkopf1（DKK1）和Dickkopf2（DKK2），最初称为WNT拮抗剂，在调节血管生成中起相反的作用。在EC形态发生过程中诱导的DKK2在培养的人内皮细胞和使用小鼠的体内测定中促进了血管生成。它的结构同源物DKK1抑制血管生成，并在诱导形态发生时被抑制。重要的是，在后肢缺血和心肌梗塞的动物模型中，局部注射DKK2蛋白可显着改善组织修复，并增强新血管形成。我们进一步表明，DKK2通过涉及LRP6介导的APC / Asef2 / Cdc42激活的信号级联反应刺激EC的飞虫动态和血管新生。因此，我们的发现证明了DKK1和DKK2在控制血管生成中的独特功能，并暗示DKK2可能是治疗缺血性血管疾病的可行治疗靶标。

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