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VEGF receptor-2-specific signaling mediated by VEGF-E induces hemangioma-like lesions in normal and in malignant tissue

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Abstract

Viral VEGF-E (ovVEGF-E), a homolog of VEGF-A, was discovered in the genome of Orf virus. Together with VEGF-A, B, C, D, placental growth factor (PlGF) and snake venom VEGF (svVEGF), ovVEGF-E is a member of the VEGF family of potent angiogenesis factors with a bioactivity similar to VEGF-A: it induces proliferation, migration and sprouting of cultured vascular endothelial cells and proliferative lesions in the skin of sheep, goat and man that are characterized by massive capillary proliferation and dilation. These biological functions are mediated exclusively via its interaction with VEGF receptor-2 (VEGFR-2). Here, we have generated transgenic mice specifically expressing ovVEGF-E in β-cells of the endocrine pancreas (Rip1VEGF-E; RVE). RVE mice show an increase in number and size of the islets of Langerhans and a distorted organization of insulin and glucagon-expressing cells. Islet endothelial cells of RVE mice hyper-proliferate and form increased numbers of functional blood vessels. In addition, the formation of disorganized lymphatic vessels and increased immune cell infiltration is observed. Upon crossing RVE single-transgenic mice with Rip1Tag2 (RT2) transgenic mice, a well-studied model of pancreatic β-cell carcinogenesis, double-transgenic mice (RT2;RVE) display hyper-proliferation of endothelial cells resulting in the formation of hemangioma-like lesions. In addition, RT2;RVE mice exhibit activated lymphangiogenesis at the tumor periphery and increased neutrophil and macrophage tumor infiltration and micro-metastasis to lymph nodes and lungs. These phenotypes markedly differ from the phenotypes observed with the transgenic expression of the other VEGF family members in β-cells of normal mice and of RT2 mice.

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Acknowledgments

We are grateful to H. Antoniadis, U. Schmieder and R. Jost for the technical support. We thank C. Dehio (Biocenter, University of Basel) for important reagents and M. Saxena (Department of Biomedicine, University of Basel) for critical comments on the manuscript. This work was supported by a Collaborative Cancer Research Project of the Swiss Cancer League (CCRP OCS-01812-12-2005) and MD-PhD fellowships to R. B. and L. K. by the Swiss National Science Foundation.

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  1. Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland

    Ernesta Fagiani, Pascal Lorentz, Ruben Bill, Kirusigan Pavotbawan, Lucie Kopfstein & Gerhard Christofori

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  1. Ernesta Fagiani
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  2. Pascal Lorentz
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  3. Ruben Bill
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Correspondence to Ernesta Fagiani.

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Fagiani, E., Lorentz, P., Bill, R. et al. VEGF receptor-2-specific signaling mediated by VEGF-E induces hemangioma-like lesions in normal and in malignant tissue. Angiogenesis 19, 339–358 (2016). https://doi.org/10.1007/s10456-016-9508-7

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  • DOI: https://doi.org/10.1007/s10456-016-9508-7

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