The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells = 혈관 내피분화에 있어 DKK2의 새로운 기능 규명

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Title
The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells = 혈관 내피분화에 있어 DKK2의 새로운 기능 규명
Author(s)
Jeong-Ki Min; H Park; H J Choi; Y Kim; B J Pyun; V Agrawal; B W Song; J Jeon; Y S Maeng; S S Rho; S Shim; J H Chai; B K Koo; H J Hong; C O Yun; C Choi; Y M Kim; K C Hwang; Y G Kwon
Bibliographic Citation
Journal of Clinical Investigation, vol. 121, no. 5, pp. 1882-1893
Publication Year
2011
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.
ISSN
0021-9738
Publisher
Amer Soc Clinical Investigation Inc
DOI
http://dx.doi.org/10.1172/JCI42556
Type
Article
Appears in Collections:
Division of Biomedical Research > Biotherapeutics Translational Research Center > 1. Journal Articles
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