Selective cyclo-oxygenase-2 inhibition induces regression of autologous endometrial grafts by down-regulation of vascular endothelial growth factor-mediated angiogenesis and stimulation of caspase-3-dependent apoptosis

Matthias W Laschke, Antje Elitzsch, Elitzsch A, Scheuer C, Claudia Scheuer, Cláudia Scheuer, Brigitte Vollmar, Vollmar B, Menger MD, Michael D Menger
Fertility and sterility · 2006 · vol. 87(1) , pp. 163–171 · doi:10.1016/j.fertnstert.2006.05.068 · PMID:17081538 · W2032459877
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Selective cyclo-oxygenase-2 inhibition causes autologous endometrial grafts to regress by reducing vascular endothelial growth factor-mediated angiogenesis and increasing caspase-3-dependent apoptosis.

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Abstract

ObjectiveTo investigate the effects of selective cyclo-oxygenase-2 (COX-2) inhibition on the angiogenesis and proliferation of endometrial grafts.DesignIntravital fluorescence microscopic study.SettingInstitute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany.AnimalsSyrian golden hamsters.InterventionsEndometrial fragments were transplanted into dorsal skinfold chambers of Syrian golden hamsters. Animals were treated daily with the selective COX-2-inhibitor NS398; controls received the vehicle dimethyl sulfoxide only.Main outcome measuresAngiogenesis was analyzed for 2 weeks with the use of intravital fluorescence microscopy. Protein expression of vascular endothelial growth factor, proliferating cell nuclear antigen, caspase-3, and activated caspase-3 was measured by Western blot analysis. Histological sections were scanned for local microthrombosis.ResultsCOX-2 inhibition induced a marked regression of endometrial grafts due to inhibition of angiogenesis, as indicated by significantly reduced microvessel density within grafts compared to controls. This effect was associated with a decreased expression of vascular endothelial growth factor. Moreover, COX-2 inhibition suppressed cell proliferation and induced apoptosis-associated caspase-3 expression. Interestingly, microthrombus formation could not be observed.ConclusionsOur study demonstrates that selective COX-2 inhibition induces regression of endometrial grafts by suppression of angiogenesis and stimulation of apoptosis. Accordingly, COX-2 inhibition may represent a novel therapeutic strategy for the treatment of endometriosis.

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MeSH descriptors

Apoptosis Caspase 3 Cyclooxygenase 2 Endometrium Graft Survival Neovascularization, Physiologic Vascular Endothelial Growth Factor A Animals Apoptosis Apoptosis Caspase 3 Cricetinae Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Cyclooxygenase 2 Inhibitors Down-Regulation Down-Regulation Endometrium Endometrium Endometrium

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