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Endothelial endostatin release is induced by general cell stress and modulated by the nitric oxide/cGMP pathway

MARTIN H. DEININGER^*,1, WOLFGANG A. WYBRANIETZ, FLORIAN T.C. GRAEPLER, ULRICH M. LAUER, RICHARD MEYERMANN^* and HERMANN J. SCHLUESENER^*

^* Institute of Brain Research, University of Tuebingen Medical School, D-72076 Tuebingen, Germany; and
Department of Internal Medicine I, Medical University Clinic Tubingen, Germany

¹Correspondence: Institute of Brain Research, University of Tuebingen Medical School, Calwer Str. 3, D-72076 Tuebingen, Germany. E-mail: martin.deininger{at}uni-tuebingen.de

Endostatin is a 20 kDa carboxyl-terminal fragment of collagen XVIII that, when added exogenously, inhibits endothelial proliferation and migration in vitro and angiogenesis and tumor growth in vivo. Previous results showed endostatin/collagen XVIII labeling in few endothelial cells in human glioblastoma multiforme. We have now observed constitutive release of endostatin from one of four endothelial cell lines. Induction of endostatin release was observed after H₂O₂, an in vitro model of cell stress, CoCl₂, a model of hypoxia, and by IFN- challenge. Endostatin expression and release was reduced by the nitric oxide synthase inhibitors aminoguanidine and L-NAME and induced by the NO synthase-independent NO donors sodium nitroprusside (SNP) and spermine-NONO-ate. SNP-mediated endostatin induction was abrogated by the soluble guanylate cyclase inhibitor 1H-(1.2.4) oxadiazolo (4,3-A) quinoxalin-1-one. Adenoviral endostatin transduction resulted in the release of endostatin from endothelial cells and in down-regulation of iNOS (NOS2) and eNOS (NOS3), and surprisingly in a 10% induction of PCNA. These results describe the modulation of endostatin release by the NO signaling cascade and provide important new pharmacological information for the systemic induction of endogenous endostatin release by common NO donor pharmacotherapy.—Deininger, M. H., Wybranietz, W. A., Graepler, F. T. C., Lauer, U. M., Meyermann, R., Schluesener, H. J. Endothelial endostatin release is induced by general cell stress and modulated by the nitric oxide/cGMP pathway.

Key Words: anti-angiogenic therapy • glioblastoma pathology • nitric oxide synthase

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