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 4

DKK2 promotes angiogenesis and improves tissue recovery in animal models of hind limb ischemia and MI.

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DKK2 promotes angiogenesis and improves tissue recovery in animal models...
(A and B) Intramuscular injection of DKK2 increased blood perfusion and reduced the probability of necrosis in the ischemic hind limb in mice. Tissue perfusion rate (%/min) was defined as the fraction of blood exchanged per minute in the vascular volume by time-series analysis of indocyanine green dye. Blood perfusion rate of the hind limb was measured at postoperative day 0 (POD 0). Correlation between regional perfusion rates of the ischemic hind limbs at POD 0 and limb necrosis levels at POD 3 was determined. The x axis shows the regional perfusion rate of the ischemic hind limbs (poor perfusion rate: 0%~30%/min; moderate perfusion rate: 30%~100%/min; good perfusion rate: 100 < %/min). Normal hind limbs typically demonstrate a perfusion rate above 400%/min. (C–J) Increase of myocardial repair after DKK2 injection. Myocardial injection of DKK2 decreased the LV infarct size as assessed by TTC staining at 1 week after MI (C and D). Representative images taken from a Masson’s trichrome–stained section (muscle is stained red, collagen is stained blue) (E and F). Microvessel staining with CD31 (G) and the TUNEL assay (I) on cardiac muscle tissues. Scale bars: 50 μm. Quantitative analysis of microvessel density and the TUNEL assay (H and J). Area with yellow broken lines (C) indicates the infarct region. Red arrows (G and I) indicate microvessels and apoptotic cells, respectively. (K) Effective improvement of cardiac function by DKK2 injection. Cardiac functions were measured with 2D conventional parameters: FS and LVEF at 3 weeks after injection of DKK2 into MI rats. FS (%) = ([LVEDD – LVESD]/LVEDD) × 100 (%). LVEDV = 7.0 × LVEDD3/(2.4 + LVEDD), LVESV = 7.0 × LVESD3/(2.4 + LVESD), and LVEF (%) = (LVEDV – LVESV)/LVEDV × 100. *P < 0.05; **P < 0.01; ***P < 0.001. S; Sham, V; VEGF, D2; DKK2. Data represent mean ± SD.