The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells
Jeong-Ki Min, … , Ki-Chul Hwang, Young-Guen Kwon
Jeong-Ki Min, … , Ki-Chul Hwang, Young-Guen Kwon
Published April 11, 2011
Citation Information: J Clin Invest. 2011;121(5):1882-1893. https://doi.org/10.1172/JCI42556.
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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

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

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Figure 3

DKK2 Tg mice exhibit increased vessel formation in the retina.

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DKK2 Tg mice exhibit increased vessel formation in the retina. (A–F) Iso...
(A–F) Isolectin B4 staining of whole-mounted P4 retinas of WT or DKK2 Tg mice (A and D). White broken lines indicate the range of vessel extension (A). Scale bars: 500 μm. White dots indicate filopodia extended from tip cells (D). Scale bars: 100 μm. Quantification of vessel densities (B), sprouting length (C), tip cell number (E), and filopodia (F). (G–I) Isolectin B4 staining of whole-mounted P12 retinas (G). Scale bars: 100 μm. Quantification of vessel density in the ganglion (first) (H) and the outer nuclear (third) cell layer (I). (J–M) Aortic segments were harvested from WT and DKK2 Tg mice (n = 7 per group). (J) Endothelial sprouts forming branching cords from the margins of aortic segments were photographed with a phase microscope. Scale bars: 200 μm. (L) Dynamic movement of endothelial sprouts from the margins of aortic segments was captured as real-time video (see Supplemental Video 1). Scale bars: 40 μm. Arrows indicate filopodia. Sprouting scores (K) and quantification of tip cell numbers (M). Sprouting scores were scored from 0 (least positive) to 5 (most positive). Data represent mean ± SD. *P < 0.05; ***P < 0.001. Box indicates 25%~75% value and whisker indicates media value in box plot (B, C, E, F, H, and I).