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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    • "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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    ABSTRACT: The blood-brain barrier (BBB) is essential for maintaining homeostasis within the central nervous system (CNS) and is a prerequisite for proper neuronal function. The BBB is localized to microvascular endothelial cells that strictly control the passage of metabolites into and out of the CNS. Complex and continuous tight junctions and lack of fenestrae combined with low pinocytotic activity make the BBB endothelium a tight barrier for water soluble moleucles. In combination with its expression of specific enzymes and transport molecules, the BBB endothelium is unique and distinguishable from all other endothelial cells in the body. During embryonic development, the CNS is vascularized by angiogenic sprouting from vascular networks originating outside of the CNS in a precise spatio-temporal manner. The particular barrier characteristics of BBB endothelial cells are induced during CNS angiogenesis by cross-talk with cellular and acellular elements within the developing CNS. In this review, we summarize the currently known cellular and molecular mechanisms mediating brain angiogenesis and introduce more recently discovered CNS-specific pathways (Wnt/β-catenin, Norrin/Frizzled4 and hedgehog) and molecules (GPR124) that are crucial in BBB differentiation and maturation. Finally, based on observations that BBB dysfunction is associated with many human diseases such as multiple sclerosis, stroke and brain tumors, we discuss recent insights into the molecular mechanisms involved in maintaining barrier characteristics in the mature BBB endothelium.
    Full-text · Article · Mar 2014 · Cell and Tissue Research
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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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    ABSTRACT: Tumor angiogenesis is essential for tumor invasive growth and metastasis, and generates abnormal vascular structures unlike developmental neovessel formation. To reduce tumor vascular abnormalities such as leakage and perivascular cell coverage deficiency that limit cancer therapy effectiveness, novel therapeutic approaches focus on vessel normalization. We have previously shown that Dickkopf-1 (DKK1), a Wnt antagonist, inhibits and its homolog DKK2 enhances, angiogenesis in normal tissues. In the present study, we investigated the effects of DKK1 and DKK2 on tumor growth and angiogenesis. Treatment of B16F10 melanoma-bearing mice with adenovirus expressing DKK1 significantly reduced tumor growth but DKK2 increased growth compared with controls. Similar pattern of tumor growth was observed in endothelial-specific DKK1 and DKK2 transgenic mice. Interestingly, tumor vascular density and perfusion were significantly decreased by DKK1 but increased by DKK2. Moreover, coverage of blood vessels by pericytes was reduced by DKK1, while DKK2 increased it. We further observed that DKK1 diminished retinal vessel density and increased avascular area in an in vivo murine model of oxygen-induced retinopathy, whereas DKK2 showed opposite results. These findings demonstrate that DKK1 and DKK2 have differential roles in normalization and functionality of tumor blood vessels, in addition to angiogenesis. Electronic supplementary material The online version of this article (doi:10.1007/s10456-013-9390-5) contains supplementary material, which is available to authorized users.
    Full-text · Article · Oct 2013 · Angiogenesis
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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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