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

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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 Dickkopfl (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 LRP6mediated APC/Asef2/Cd.c42 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.
Publisher
AMER SOC CLINICAL INVESTIGATION INC
Issue Date
2011-05
Language
English
Article Type
Article
Keywords

GROWTH-FACTOR; SIGNALING PATHWAY; VASCULAR MORPHOGENESIS; HINDLIMB ISCHEMIA; EXCHANGE FACTOR; HEAD INDUCTION; TUMOR-GROWTH; STEM-CELLS; NOTCH; RECEPTOR

Citation

JOURNAL OF CLINICAL INVESTIGATION, v.121, no.5, pp.1882 - 1893

ISSN
0021-9738
DOI
10.1172/JCI42556
URI
http://hdl.handle.net/10203/97194
Appears in Collection
BiS-Journal Papers(저널논문)
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