The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells

Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
The Journal of clinical investigation (Impact Factor: 13.22). 05/2011; 121(5):1882-93. DOI: 10.1172/JCI42556
Source: PubMed


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.

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Article: The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells

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    • "Furthermore, enforced Wnt/β-catenin signaling augmented mural cell recruitment, thereby contributing to vascular quiescence and barrier function. Although these studies suggest that reinforced Wnt/β-catenin signaling in brain tumor vessels leads to an inhibition of angiogenesis with normalized and less permeable vessels, studies in other experimental tumors highlight a proangiogenic function of the Wnt//β-catenin pathway (Min et al. 2011). Currently, the determinants of the outcome of Wnt/β-catenin signaling are unknown in the vascular compartment in general and in the BBB endothelium in particular. "
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    Cell and Tissue Research 03/2014; 355(3). DOI:10.1007/s00441-014-1811-2 · 3.57 Impact Factor
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    • "DKK1 inhibits human umbilical vein endothelial cell (EC) tube formation and proliferation by reducing both Wnt/beta-catenin and DKK2/cell division-control protein 42 (CDC42) signaling activity. Transgenic mice that selectively overexpress murine DKK1 in ECs (DKK1 Tg) show retarded retinal and bone angiogenesis [8, 9]. Conversely, DKK2, a DKK1-homolog, enhances EC migration by activating CDC42 independent of Wnt. "
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    Angiogenesis 10/2013; 17(1). DOI:10.1007/s10456-013-9390-5 · 4.88 Impact Factor
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    • "In an earlier report from our laboratory, it was demonstrated that cytoplasmic β-catenin and Dvl-1 expression were located in the endothelial cells of the newly formed and pre-existing blood vessels of the infarcted area one week post-MI, whereas this was not observed in the rest of the heart [73]. More recently, local administration of DKK-2 in the infarcted heart has been shown to enhance neovascularization [74]. This implies that impairment of Wnt/Frizzled signaling ameliorates formation of new vessels. "
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