Hum. Reprod. Advance Access originally published online on February 3, 2009
Human Reproduction 2009 24(5):1025-1035; doi:10.1093/humrep/den499
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Dopamine agonist administration causes a reduction in endometrial implants through modulation of angiogenesis in experimentally induced endometriosis
1 Instituto Valenciano de Infertilidad (IVI), University of Valencia, Plaza de la Policía Local, 3, 46015 Valencia, Spain 2 Department of Pathology, University of Valencia, Valencia, Spain 3 Research Unit, School of Medicine and Odontology, University of Valencia, Valencia, Spain
4 Correspondence address. E-mail: apellicer{at}ivi.es
BACKGROUND: Implantation of a retrogradely-shed endometrium during menstruation requires an adequate blood supply. The endometrium has angiogenic potential, and endometriotic lesions grow in areas with a rich vascularization, suggesting that angiogenesis is a prerequisite for endometriosis development. Targeting vascular endothelial growth factor (VEGF) leads to an inhibition of endometriosis. Dopamine and its agonists, such as cabergoline (Cb2), promote VEGF receptor-2 (VEGFR-2) endocytosis in endothelial cells, preventing VEGF–VEGFR-2 binding and reducing neoangiogenesis. The aim of this study was to evaluate the anti-angiogenic properties of Cb2 on growth of established endometriosis lesions and investigate the molecular mechanisms by which Cb2 exerts the anti-angiogenic effect.
METHODS: Human endometrium fragments were implanted in female nude mice peritoneum, and mice were treated with vehicle, 0.05 or 0.1 mg/kg/day oral Cb2 for 14 days. After treatment, the implants were processed to assess proliferative activity, neoangiogenesis, VEGFR-2 phosphorylation and angiogenic gene expression.
RESULTS: A significant decrease in the percentage of active endometriotic lesions (P < 0.05) and cellular proliferation index (P < 0.001) was found with Cb2 treatment. Neoangiogenesis was reduced by Cb2 treatment, as observed at gross morphological level and by significant changes in gene expression. The degree of VEGFR-2 phosphorylation was significantly lower in Cb2-treated animals than controls.
CONCLUSIONS: Cb2 treatment in experimental endometriosis has an anti-angiogenic effect acting through VEGFR-2 activation. These findings support the testing of dopamine agonists as a novel therapeutic approach to peritoneal endometriosis in humans.
Key words: endometriosis/dopamine agonists/cabergoline/angiogenesis/vascular endothelial growth factor
Submitted on August 8, 2008; resubmitted on December 15, 2008; accepted on December 28, 2008.