title: The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells.
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.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Jeong-Ki
authors.initials: JK
authors.lastname: Min
authors.forename: Hongryeol
authors.initials: H
authors.lastname: Park
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Choi
authors.forename: Yonghak
authors.initials: Y
authors.lastname: Kim
authors.forename: Bo-Jeong
authors.initials: BJ
authors.lastname: Pyun
authors.forename: Vijayendra
authors.initials: V
authors.lastname: Agrawal
authors.forename: Byeong-Wook
authors.initials: BW
authors.lastname: Song
authors.forename: Jongwook
authors.initials: J
authors.lastname: Jeon
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Maeng
authors.forename: Seung-Sik
authors.initials: SS
authors.lastname: Rho
authors.forename: Sungbo
authors.initials: S
authors.lastname: Shim
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Chai
authors.forename: Bon-Kyoung
authors.initials: BK
authors.lastname: Koo
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Hong
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
authors.forename: Chulhee
authors.initials: C
authors.lastname: Choi
authors.forename: Young-Myoung
authors.initials: YM
authors.lastname: Kim
authors.forename: Ki-Chul
authors.initials: KC
authors.lastname: Hwang
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology*; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007511:Ischemia / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology; D009389:Neovascularization, Pathologic; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014470:Umbilical Cord / Q000166:cytology; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: C501126:DKK1 protein, human; C498622:DKK2 protein, human; C501127:Dkk1 protein, mouse; C531384:Dkk1 protein, rat; C405060:Dkk2 protein, mouse; C504269:Dkk2 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D051153:Wnt Proteins