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
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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Research Article Angiogenesis

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 5

DKK2 increases filopodial protrusions in a Cdc42-dependent manner.

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DKK2 increases filopodial protrusions in a Cdc42-dependent manner. (A) H...
(A) HUVECs stably expressing eGFP, DKK1, or DKK2 were analyzed for Cdc42 activities. (B) Stable transfectants were cultured on Matrigel-coated plate (morphogenesis) for 2 hours and Cdc42 activities were measured. (C and D) HUVECs were transiently transfected with expression plasmids encoding eGFP control or eGFP dominant negative mutant of Cdc42 (Cdc42 N17). After 24 hours, these cells were plated on Matrigel-coated plates and incubated with PBS or DKK2 (1.5 μg/ml) for 2 hours. Then microphotographs were taken (C) and filopodia number was quantified (D). Arrowheads indicate filopodial extension. Data represent mean ± SD. **P < 0.01. Scale bars: 20 μm. (E) HUVECs stably expressing eGFP or DKK2 were incubated with sFRP (200 ng/ml) for 24 hours and Cdc42 activity was measured.