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

Research output: Contribution to journalArticle

63 Citations (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.

Original languageEnglish
Pages (from-to)1882-1893
Number of pages12
JournalJournal of Clinical Investigation
Volume121
Issue number5
DOIs
Publication statusPublished - 2011 May 2

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    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. (2011). The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells. Journal of Clinical Investigation, 121(5), 1882-1893. https://doi.org/10.1172/JCI42556