한빛사논문
- 조회4,240
Abstract
Jeong-Ki Min1,2, Hongryeol Park1, Hyun-Jung Choi1, Yonghak Kim1, Bo-Jeong Pyun1,3, Vijayendra Agrawal1, Byeong-Wook Song4, Jongwook Jeon5, Yong-Sun Maeng1, Seung-Sik Rho1, Sungbo Shim6, Jin-Ho Chai1, Bon-Kyoung Koo7, Hyo Jeong Hong2, Chae-Ok Yun8, Chulhee Choi5, Young-Myoung Kim9, Ki-Chul Hwang4 and Young-Guen Kwon1
1Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
2Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
3College of Pharmacy and Division of Life Science and Pharmaceuticals, Ewha Womans University, Seoul, Republic of Korea.
4Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
5Cell Signaling and Bioimaging Laboratory, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
6Department of Biological Science, Sookmyung Women’s University, Yongsan-Ku, Seoul, Republic of Korea.
7Department of Biological Sciences, Seoul National University, Silim-dong, Gwanak-gu, Seoul, Republic of Korea.
8Brain Korea 21 Project for Medical Science, Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
9Vascular System Research Center, Kangwon National University, Kangwon-Do, Republic of Korea.
Address correspondence to: Young-Guen Kwon
Authorship note: Jeong-Ki Min and Hongryeol Park contributed equally to this work.
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.
논문정보
- Research article
- 2011년 04월 (BRIC 등록일 )
- 국내 연구진
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