Endothelial endostatin release is induced by general cell stress and modulated by the nitric oxide/cGMP pathway.
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-gamma 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
Martin H
MH
Institute of Brain Research, University of Tuebingen Medical School, Calwer Str. 3, D-72076 Tuebingen, Germany. martin.deininger@uni-tuebingen.de
Wybranietz
Wolfgang A
WA
Graepler
Florian T C
FT
Lauer
Ulrich M
UM
Meyermann
Richard
R
Schluesener
Hermann J
HJ
D000328:Adult; D000368:Aged; D000818:Animals; D001921:Brain / Q000166:cytology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D002460:Cell Line; D003094:Collagen / Q000032:analysis / Q000378:metabolism*; D043170:Collagen Type XVIII; D006152:Cyclic GMP / Q000502:physiology*; D043169:Endostatins; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D016877:Oxidants / Q000494:pharmacology; D010446:Peptide Fragments / Q000032:analysis / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D043170:Collagen Type XVIII; D043169:Endostatins; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D016877:Oxidants; D010446:Peptide Fragments; D009569:Nitric Oxide; D007371:Interferon-gamma; D003094:Collagen; D006861:Hydrogen Peroxide; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat; D006162:Guanylate Cyclase; D006152:Cyclic GMP