Dopamine agonist administration causes a reduction in endometrial implants through modulation of angiogenesis in experimentally induced endometriosis

Author： Novella-Maestre Edurne Carda Carmen Noguera Inmaculada Ruiz-Saur Amparo Garca-Velasco Juan Antonio Simn Carlos Pellicer Antonio

Publisher： Oxford University Press

ISSN： 1460-2350

Source： Human Reproduction, Vol.24, Iss.5, 2009-05, pp. : 1025-1035

Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.

Previous Menu Next

Abstract

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 VEGFVEGFR-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=""> 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.