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  • Original Article
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Nf1 haploinsufficiency augments angiogenesis

Oncogene volume 25, pages 2297–2303 (2006)Cite this article

Abstract

Mutations in the NF1 tumor-suppressor gene underlie neurofibromatosis type 1 (NF1), in which patients are predisposed to certain tumors such as neurofibromas and may associate with vascular disorder. Plexiform neurofibromas are slow growing benign tumors that are highly vascular and can progress to malignancy. The development of neurofibromas requires loss of both Nf1 alleles in Schwann cells destined to become neoplastic and may be exacerbated by Nf1 heterozygosity in other non-neoplastic cells. This study tested the hypothesis that Nf1 heterozygosity exaggerates angiogenesis. We found that Nf1 heterozygous mice showed increased neovascularization in both the retina and cornea in response to hypoxia and bFGF, respectively, compared to their wild-type littermates. The increase in corneal neovascularization was associated with heightened endothelial cell proliferation and migration, and increased infiltration of inflammatory cells. In addition, Nf1 heterozygous endothelial cell cultures showed an exaggerated proliferative response to angiogenic factors, particularly to bFGF. These findings support the conclusion that Nf1 heterozygosity in endothelial cells and perhaps inflammatory cells augments angiogenesis, which may promote neurofibroma formation in NF1.

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Acknowledgements

We thank Drs William Hauswirth and Maria Grant for guidance in developing the retinal NV model. Elizabeth Baldwin, Hua Li, Fredrick Kweh and Debbie Neubauer, provided excellent technical assistance. This work was supported by US Army Neurofibromatosis Research Program Grants DAMD170310224 (DM) and DAMD170110707 (MRW).

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Authors and Affiliations

  1. Department of Pediatrics, Division of Neurology, University of Florida, Gainesville, FL, USA

    M Wu & D Muir

  2. Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA

    M R Wallace

  3. McKnight Brain Institute and UF Shands Cancer Center, University of Florida, Gainesville, FL, USA

    M R Wallace & D Muir

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  1. M Wu
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Correspondence to M Wu.

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Wu, M., Wallace, M. & Muir, D. Nf1 haploinsufficiency augments angiogenesis. Oncogene 25, 2297–2303 (2006). https://doi.org/10.1038/sj.onc.1209264

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