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Soluble neuropilin targeted to the skin inhibits vascular permeability

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Abstract

Neuropilin 1 (NRP1) is a co-receptor for vascular endothelial growth factor (VEGF165), an inducer of vascular permeability and angiogenesis. Numerous physiological factors enhance VEGF expression and function but only a few have been shown to be negative regulators. Previously, we have shown that the naturally occurring soluble form of NRP1 (sNRP1) inhibits binding of VEGF165 to endothelial cells in vitro and impairs tumor growth in vivo. To investigate the role of sNRP1 in the regulation of vascular development and function, sNRP1 expression was targeted to the skin, where it is not normally expressed, using a keratin 14 (K14) promoter expression construct. K14-sNRP1 transgenic mice displayed normal skin architecture with a subtle abnormal vascular phenotype. While the overall number of skin blood vessels remained unchanged, the lumen size of smooth muscle-associated dermal vessels was reduced. K14-sNRP1 mice had reduced vascular permeability in response to VEGF165, but also to VEGF121 and platelet activating factor, suggesting that the lack of permeability was not solely due to the sequestration of VEGF. sNRP1 also reversed the increase in inflammation and edema induced by transgenic VEGF overexpression in cutaneous delayed-type hypersensitivity reactions. In summary, sNRP1 appears to primarily regulate vessel permeability while its effect on physiological angiogenesis is less evident in this model.

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Abbreviations

DTH:

delayed-type hypersensitivity

EC:

endothelial cell

EGF:

epidermal growth factor

FGF:

fibroblast growth factor

H&E:

hematoxylin and eosin

HIF:

hypoxia inducible factor

K1:

keratin 1

K14:

keratin 14

NRP1:

neuropilin 1

PlGF:

placenta growth factor

PAF:

platelet activating factor

SMA:

smooth muscle actin

sNRP1:

soluble neuropilin 1

Tg:

transgenic

TC:

trichrome

VEGF/VPF:

vascular endothelial growth factor/vascular permeability factor

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Acknowledgements

This work was supported by NIH grants CA37392 and CA45548 and the Harvard Skin Disease Research Center (M.K.), NIH grants CA69184, CA86410 and CA92644 (M.D.), a grant from the Ernst Schering Research Foundation in Berlin, Germany (R.M.), and the George & Elizabeth Sanborn Foundation Fellowship through the American Cancer Society (D.R.B.). The authors thank Drs. Elazar Zelzer and Nava Almog for helpful discussions and critical reading of the manuscript. We also thank Ricky Sanchez, Hetty Eisenberg, Lauren Janes, Paula Velasco, and Lin Wu for technical assistance and Kristen Gullage for photography and graphic design.

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  1. Roni Mamluk

    Present address: Compound Therapeutics, Waltham, Massachusetts, USA

Authors and Affiliations

  1. Vascular Biology Program, Children’s Hospital and Harvard Medical School, Karp Family Research Building, Boston, Massachusetts, USA

    Roni Mamluk, Michael Klagsbrun & Diane R. Bielenberg

  2. Departments of Surgery, Children’s Hospital and Harvard Medical School, Karp Family Research Building, Boston, Massachusetts, USA

    Roni Mamluk, Michael Klagsbrun & Diane R. Bielenberg

  3. Departments of Pathology, Children’s Hospital and Harvard Medical School, Karp Family Research Building, Boston, Massachusetts, USA

    Michael Klagsbrun

  4. Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Michael Detmar

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  1. Roni Mamluk
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Correspondence to Michael Klagsbrun.

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Mamluk, R., Klagsbrun, M., Detmar, M. et al. Soluble neuropilin targeted to the skin inhibits vascular permeability. Angiogenesis 8, 217–227 (2005). https://doi.org/10.1007/s10456-005-9009-6

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  • DOI: https://doi.org/10.1007/s10456-005-9009-6

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