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Long-term blockade of nitric oxide synthesis in rats modulates coronary capillary network remodeling

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Abstract

Long-term blockade of nitric oxide synthesis with Nω-nitro-L-arginine methyl ester (L-NAME) induces cardiac perivascular fibrosis in rats. Its relationship to expression of angiogenic growth factors and capillary network remodeling is not understood. This study was designed to determine whether capillary proliferation and angiogenic growth factor regulation occur in response to L-NAME. Three groups of rats were studied: C, control; L1, L-NAME 13 mg/kg/day; L2, 130 mg/kg/day. One and eight weeks later the hearts were removed and subjected to morphometric analysis and analysis of gene expressions of molecules related to angiogenesis. Arterial hypertension was observed within 8 weeks in the L1 and L2 groups compared with control. After 1 week immunohistochemical assays demonstrated basic fibroblast growth factor (bFGF) in the arteriolar media. Northern blot analysis revealed increase in bFGF and transforming growth factor-β (TGF-β) mRNA during this period. At 8 weeks arteriolar medial thickening and perivascular fibrosis were seen microscopically in the L1 and L2 groups, which were accompanied by only a modest remodeling of capillary network due to increase in venular or intermediate capillary portions. Concomitantly immunoreactivity for vascular endothelial growth factor (VEGF) and TGF-β were detected in perivascular area. These results suggest that (1) blockade of NO synthesis induces expression of angiogenic growth factors as well as vessel wall remodeling, and (2) TGF-β may counteract angiogenic growth factors and limit subsequent alterations in capillary network remodeling.

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan

    Daisuke Goto, Satoshi Fujii, A.K.M. Tarikuz Zaman, Ichiro Sakuma & Akira Kitabatake

  2. Research Institute for Electronic Sciences, Hokkaido University, Sapporo, Japan

    Ming Gao & Tomiyasu Koyama

  3. Department of Molecular Physiology and Biophysics, University of Vermont College of Medicine, Burlington, Vermont, USA

    John Mitchell

  4. Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA

    Janet Woodcock-Mitchell & Burton E. Sobel

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  1. Daisuke Goto
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  2. Satoshi Fujii
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  4. Ichiro Sakuma
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Goto, D., Fujii, S., Zaman, A.T. et al. Long-term blockade of nitric oxide synthesis in rats modulates coronary capillary network remodeling. Angiogenesis 3, 137–146 (1999). https://doi.org/10.1023/A:1009050131966

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