Pro-inflammatory angiogenesis is mediated by p38 MAP kinase

Authors

  • Gangaraju Rajashekhar,

    Corresponding author
    1. Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana
    2. Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, Indiana
    • Department of Ophthalmology and Cellular and Integrative Physiology, Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, VA Medical Center—C 3125, 1481 West 10th Street, Indianapolis, IN 46202.
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  • Malgorzata Kamocka,

    1. Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, Indiana
    2. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
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  • Abby Marin,

    1. Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana
    2. Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, Indiana
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  • Mark A. Suckow,

    1. Freimann Life Science Center, University of Notre Dame, Notre Dame, Indiana
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  • William R. Wolter,

    1. Freimann Life Science Center, University of Notre Dame, Notre Dame, Indiana
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  • Sunil Badve,

    1. IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana
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  • Aravind Raj Sanjeevaiah,

    1. Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, Indiana
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  • Kevin Pumiglia,

    1. Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York
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  • Elliot Rosen,

    1. Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, Indiana
    2. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
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  • Matthias Clauss

    1. Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana
    2. Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, Indiana
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Abstract

Chronic inflammation is tightly linked to diseases associated with endothelial dysfunction including aberrant angiogenesis. To better understand the endothelial role in pro-inflammatory angiogenesis, we analyzed signaling pathways in continuously activated endothelial cells, which were either chronically exposed to soluble TNF or the reactive oxygen species (ROS) generating H2O2, or express active transmembrane TNF. Testing in an in vitro capillary sprout formation assay, continuous endothelial activation increased angiogenesis dependent on activation of p38 MAP kinase, NADPH oxidase, and matrix metalloproteinases (MMP). p38 MAP kinase- and MMP-9-dependent angiogenesis in our assay system may be part of a positive feed forward autocrine loop because continuously activated endothelial cells displayed up-regulated ROS production and subsequent endothelial TNF expression. The pro-angiogenic role of the p38 MAP kinase in continuously activated endothelial cells was in stark contrast to the anti-angiogenic activity of the p38 MAP kinase in unstimulated control endothelial cells. In vivo, using an experimental prostate tumor, pharmacological inhibition of p38 MAP kinase demonstrated a significant reduction in tumor growth and in vessel density, suggesting a pro-angiogenic role of the p38 MAP kinase in pathological angiogenesis in vivo. In conclusion, our results suggest that continuous activation of endothelial cells can cause a switch of the p38 MAP kinase from anti-angiogenic to pro-angiogenic activities in conditions which link oxidative stress and autocrine TNF production. J. Cell. Physiol. 226: 800–808, 2011. © 2010 Wiley-Liss, Inc.

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