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.
OBJECTIVE
To investigate the effects of selective cyclo-oxygenase-2 (COX-2) inhibition on the angiogenesis and proliferation of endometrial grafts.


METHODS
Intravital fluorescence microscopic study.


METHODS
Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany.


METHODS
Syrian golden hamsters.


METHODS
Endometrial 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.


METHODS
Angiogenesis 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.


RESULTS
COX-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.


CONCLUSIONS
Our 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.
Laschke
Matthias W
MW
Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany. matthias.laschke@uniklinik-saarland.de <matthias.laschke@uniklinik-saarland.de>
Elitzsch
Antje
A
Scheuer
Claudia
C
Vollmar
Brigitte
B
Menger
Michael D
MD
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism*; D006224:Cricetinae; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage; D015536:Down-Regulation / Q000187:drug effects; D004717:Endometrium / Q000166:cytology / Q000187:drug effects / Q000502:physiology* / Q000637:transplantation; D005260:Female; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008647:Mesocricetus; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D052246:Cyclooxygenase 2 Inhibitors; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; D053148:Caspase 3