Scientists have identified the WNT antagonist dickkopf2 (DKK2) as a potential new target for the treatment of ischemic vascular diseases. The Yonsei University researchers in Seoul, Korea, found that the structurally related proteins dicckopf1 (DKK1) and DKK2 actually play opposing functional roles in regulating angiogenesis. Their studies showed that while DKK2 promotes angiogenesis in cultured human endothelial cells and in vivo mouse assays, its structural homologue DKK1 suppresses angiogenesis and is repressed upon the induction of morphogenesis in vitro.
The team subsequently found that local injection of DKK2 protein significantly improved tissue repair and boosted neovascularization in animal models of both hind limb ischemia and myocardial infarction. They suggest that DKK2 may therefore represent a promising new therapeutic target for the treatment of ischemic vascular disease. The research is published in the Journal of Clinical Investigation in a paper titled, “The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells.”
Neovessel formation is a complex process governed by the orchestrated action of multiple factors that are being widely exploited to develop new treatments for angiogenesis-related diseases such as diabetic retinopathy and tumor growth and metastasis, reports the Seoul team, led by Young-Guen Kwon, Ph.D., at Yonsei University’s College of Life Science and Biotechnology. WNT signaling is one of the pathways that has been implicated in the regulation and development of the vascular system, and numerous studies have demonstrated diverse roles of WNT signaling in regulating embryonic cell functions such as proliferation, survival, differentiation, cell junctions, and polarity. However, they admit, the detailed mechanisms of this process have so far remained unclear.
In vitro studies by Dr. Kwon and colleagues have now found that the WNT pathway inhibitors DKK1 and DKK2 are differentially expressed in embryonic cells during morphogenetic differentiation and play opposite functions in regulating angiogenesis. Their studies found that DKK1 is rapidly downregulated upon inducing morphogenesis of cells on 2D Matrigel, whereas DKK2 is upregulated during this process. Production of DKK2 appeared to be rapidly induced by embryonic cell recognition of laminins.
Subsequent studies in rodents showed that intramuscular injection of DKK2 resulted in a significant reduction in necrosis in a mouse model of hind limb ischemia, due to improved neovascularization in the limb. In a rat model of myocardial infarction, an injection of DKK2 protein significantly reduced the infarct size and the degree of fibrosis in the infarct zone. “Given that DKK2 is a relatively small and soluble ligand, our finding that DKK2 alone can induce new and functional vessel formation in vivo may provide a novel strategy for developing therapeutic strategies to treat ischemic vascular diseases,” the researchers conclude.