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Wnt2 acts as an angiogenic growth factor for non-sinusoidal endothelial cells and inhibits expression of stanniocalcin-1

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Abstract

Recently, we have shown that Wnt2 is an autocrine growth and differentiation factor for hepatic sinusoidal endothelial cells. As Wnt signaling has become increasingly important in vascular development and cancer, we analyzed Wnt signaling in non-sinusoidal endothelial cells of different vascular origin (HUVEC, HUAEC, HMVEC-LLy). Upon screening the multiple components of the Wnt pathway, we demonstrated lack of Wnt2 expression, but presence of Frizzled-4, one of its receptors, in cultured non-sinusoidal endothelial cells. Treatment of these cells by exogenous Wnt2 induced endothelial proliferation and sprouting angiogenesis in vitro. Upon analysis of Wnt2 tissue expression as a basis for paracrine Wnt2 effects on non-sinusoidal endothelial cells in vivo, Wnt2 was found to be expressed in densely vascularized murine malignant tumors and in wound healing tissues in close proximity to CD31+ endothelial cells. By gene profiling, stanniocalcin-1 (STC1), a known regulator of angiogenesis, was identified as a target gene of Wnt2 signaling in HUVEC down-regulated by Wnt2 treatment. Tumor-conditioned media counter-acted Wnt2 and up-regulated STC1 expression in HUVEC. In conclusion, we provide evidence that Wnt2 acts as an angiogenic factor for non-sinusoidal endothelium in vitro and in vivo whose target genes undergo complex regulation by the tissue microenvironment.

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Acknowledgments

Grant support: The work was supported by the Deutsche Forschungsgemeinschaft [SFB TR 23, (S.G. and B.A.); European Graduate College GRK 880/2 (S.G.)] and by the Tumor Centre Heidelberg/Mannheim (S.G. and B.A.). The authors state that there are no personal or institutional conflicts of interest.

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Authors and Affiliations

  1. Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany

    Diana Klein, Alexandra Demory, Francis Peyre, Cyrill Géraud, Nils Ohnesorge, Kai Schledzewski & Sergij Goerdt

  2. Department of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany

    Bernd Arnold

  3. Joint Research Division Vascular Biology, Medical Faculty Mannheim, University of Heidelberg, and German Cancer Research Center, Heidelberg, Germany

    Jens Kroll

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  1. Diana Klein
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  2. Alexandra Demory
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Correspondence to Diana Klein.

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Klein, D., Demory, A., Peyre, F. et al. Wnt2 acts as an angiogenic growth factor for non-sinusoidal endothelial cells and inhibits expression of stanniocalcin-1. Angiogenesis 12, 251–265 (2009). https://doi.org/10.1007/s10456-009-9145-5

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