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

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 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.

• Authors: Edurne Novella-Maestre, Carmen Carda, Inmaculada Noguera, Amparo Ruiz-Saurí, Juan Antonio García-Velasco, Carlos Simón, Antonio Pellicer
• Journal: Human reproduction (Oxford, England) (Hum Reprod) Vol. 24 Issue 5 Pg. 1025-35 (May 2009) ISSN: 1460-2350 [Electronic] England
• PMID: 19189995 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dopamine Agonists
• Ergolines
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor Receptor-2
• Cabergoline

Topics

• Animals
• Cabergoline
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Dopamine Agonists (therapeutic use)
• Endometriosis (drug therapy, pathology)
• Ergolines (therapeutic use)
• Female
• Gene Expression Regulation (drug effects)
• Humans
• Mice
• Neovascularization, Pathologic (drug therapy, genetics)
• Phosphorylation (drug effects)
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)