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Nitric oxide modulates hepatocyte growth factor/scatter factor-induced angiogenesis

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Abstract

Objective: There is limited knowledge about potential therapeutic targets in Hepatocyte growth factor/scatter factor (HGF)-induced pathophysiological angiogenesis. Recent candidates have included phosphatidylinositol-3-kinase, which is an upstream activator for endothelial nitric oxide (NO) synthase (NOS III). The current study is the first to evaluate the possible involvement of NOS-NO cascade in HGF-induced angiogenesis. Methods and results: NOS III inhibitors blocked the HGF-induced functional neovascularization in vivo, as quantified using vessel counts, 133Xe-clearance, and immunohistology. This was reversed by L-arginine. Western blot analysis of HGF-treated cells also revealed a temporal increase in HGF-induced phosphorylation. In a deconstructional approach, HGF induced the proliferation and chemokinesis of human endothelial cells. These phenotypic effects were inhibited by NOS inhibitors, L-NAME and L-NIO, and the NO scavenger, carboxy PTIO, but unaltered by 1400W, a NOS II inhibitor. This inhibition was reversed by spermine NONOate, a NO donor, which independently exerted a biphasic effect on endothelial cell proliferation. The modulation of NO did not alter HGF-induced chemoinvasion of endothelial cells, while spermine-NONOate destabilized HGF-induced tubulogenesis, suggesting that a single assay is not sufficient for predicting the final phenotypic outcome on angiogenesis. Conclusions: The study is the first to demonstrate that the NOS III nitric oxide is a key signal cascade in HGF-induced angiogenesis, and represents a promising target for the clinical management of pathological conditions characterized by overt HGF signaling.

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Authors and Affiliations

  1. Department of Pharmacology, Angiogenesis Laboratory, UK

    Shiladitya Sengupta & Tai-Ping D. Fan

  2. Babraham Institute, Cambridge, UK

    Lynda A. Sellers

  3. Department of Oncology, University of Cambridge, MRC-Laboratory of Molecular Biology, Cambridge, UK

    Ermanno Gherardi

  4. Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Shiladitya Sengupta & Ram Sasisekharan

Authors
  1. Shiladitya Sengupta
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  2. Lynda A. Sellers
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  3. Ermanno Gherardi
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  4. Ram Sasisekharan
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  5. Tai-Ping D. Fan
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Correspondence to Shiladitya Sengupta.

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Sengupta, S., Sellers, L.A., Gherardi, E. et al. Nitric oxide modulates hepatocyte growth factor/scatter factor-induced angiogenesis. Angiogenesis 7, 285–294 (2004). https://doi.org/10.1007/s10456-004-5238-3

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  • DOI: https://doi.org/10.1007/s10456-004-5238-3

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