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

Title
The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells
Authors
Min J.-K.Park H.Choi H.-J.Kim Y.Pyun B.-J.Agrawal V.Song B.-W.Jeon J.Maeng Y.-S.Rho S.-S.Shim S.Chai J.-H.Koo B.-K.Hong H.J.Yun C.-O.Choi C.Kim Y.-M.Hwang K.-C.Kwon Y.-G.
Ewha Authors
편보정
Issue Date
2011
Journal Title
Journal of Clinical Investigation
ISSN
0021-9738JCR Link
Citation
vol. 121, no. 5, pp. 1882 - 1893
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
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. Copyright © 2011, The American Society for Clinical Investigation.
DOI
10.1172/JCI42556
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연구기관 > 약학연구소 > Journal papers
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