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Updated: May 11, 2026
Rat Mesentery Angiogenesis Assay
Published on: June 18, 2011
The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells
Jeong-Ki Min1, Hongryeol Park, Hyun-Jung Choi
1Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
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.
Insights
Dickkopf2 (DKK2) promotes new blood vessel formation (angiogenesis), aiding tissue repair in conditions like heart attack and limb ischemia. Its counterpart, Dickkopf1 (DKK1), inhibits this process, revealing distinct roles for these WNT antagonists.
Area of Science:
- Vascular Biology
- Molecular Signaling
- Regenerative Medicine
Background:
- Angiogenesis, or new blood vessel formation, is crucial for development and disease, involving complex signaling pathways.
- WNT signaling is known to influence vascular development, but its precise roles and regulators are not fully understood.
- Dickkopf proteins (DKK1 and DKK2) are established WNT antagonists, but their specific functions in angiogenesis remain unclear.
Purpose of the Study:
- To elucidate the distinct roles of Dickkopf1 (DKK1) and Dickkopf2 (DKK2) in regulating angiogenesis.
- To investigate the therapeutic potential of DKK2 in promoting neovascularization and tissue repair.
Main Methods:
- In vitro studies using cultured human endothelial cells (ECs) to assess DKK2's effect on angiogenesis.
- In vivo mouse models for evaluating DKK2's efficacy in promoting neovascularization and tissue repair in hind limb ischemia and myocardial infarction.
- Analysis of the signaling cascade downstream of DKK2, including LRP6-mediated activation of APC/Asef2/Cdc42.
Main Results:
- DKK2 significantly promoted angiogenesis in ECs and in vivo assays.
- DKK1 suppressed angiogenesis, and its expression was downregulated during EC morphogenesis.
- Local administration of DKK2 protein enhanced tissue repair and neovascularization in animal models of ischemic diseases.
- DKK2 was shown to stimulate EC filopodial dynamics and angiogenic sprouting through a specific signaling pathway.
Conclusions:
- DKK1 and DKK2 exhibit opposing functions in regulating angiogenesis.
- DKK2 acts as a pro-angiogenic factor, stimulating ECs via the LRP6/APC/Asef2/Cdc42 pathway.
- DKK2 represents a promising therapeutic target for treating ischemic vascular diseases and promoting tissue regeneration.
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