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

 Jeong-Ki Min  ;  Hongryeol Park  ;  Hyun-Jung Choi  ;  Yonghak Kim  ;  Bo-Jeong Pyun  ;  Vijayendra Agrawal  ;  Byeong-Wook Song  ;  Jongwook Jeon  ;  Yong-Sun Maeng  ;  Seung-Sik Rho  ;  Sungbo Shim  ;  Jin-Ho Chai  ;  Bon-Kyoung Koo  ;  Hyo Jeong Hong  ;  Chae-Ok Yun  ;  Chulhee Choi  ;  Young-Myoung Kim  ;  Ki-Chul Hwang  ;  Young-Guen Kwon 
 JOURNAL OF CLINICAL INVESTIGATION, Vol.121(5) : 1882-1893, 2011 
Journal Title
Issue Date
Animals ; Aorta/metabolism ; Endothelial Cells/cytology* ; Gene Expression Regulation* ; Humans ; Intercellular Signaling Peptides and Proteins/metabolism* ; Ischemia/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Myocardial Infarction/pathology ; Neovascularization, Pathologic* ; Proteins/metabolism* ; Rats ; Rats, Sprague-Dawley ; Umbilical Cord/cytology ; Wnt Proteins/metabolism*
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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5. Research Institutes (연구소) > Institute for Cancer Research (암연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Song, Byeong Wook(송병욱)
Yun, Chae Ok(윤채옥)
Hwang, Ki Chul(황기철)
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