Dopamine Agonist Administration Causes a Reduction in Endometrial Implants Through Modulation of Angiogenesis in Experimentally Induced Endometriosis

Survival of newly implanted retrograde–shed endometrial tissue during menstruation in an ectopic location requires an adequate blood supply. This suggests that angiogenesis is a prerequisite for the development of endometriosis and that its inhibition may be a target for preventing development. Previous studies have shown that vascular endothelial growth factor (VEGF), a heparin-binding glycoprotein, has an essential role in angiogenesis. The main regulatory factor for angiogenesis appears to be binding of VEGF to its type-2 receptor (VEGFR-2). Cabergoline (Cb2) and other dopamine agonists promote endocytosis of the VEGF receptor-2 (VEGFR-2) in endothelial cells, thereby preventing VEGF–VEGFR-2 binding and reducing neoangiogenesis. This study used an experimental model of endometriosis to assess the anti-angiogenic effects of Cb2 at the morphological level on growth of established endometriotic lesions and to investigate molecular mechanisms associated with these effects. The investigators implanted human endometrial sections in the peritoneum of nude mice and divided the mice into 3 groups which received by gavage either Cb2 in daily oral doses of 0.05 (low-dose group) or 0.1 (high-dose group) mg/kg, or a control vehicle for 14 days. After treatment, the implants were processed to compare proliferative activity, the neoangiogenic process, angiogenic gene expression, and VEGFR-2 phosphorylation in the 3 groups. Compared with the controls, there was a significant decrease in the percentage of active endometriotic lesions in both Cb2-treated groups (P < 0.05). The cellular proliferation index was also decreased (P < 0.001). Histology showed intact lesions in the controls, whereas the Cb2-treated lesions had a lack of cellularity and organization characteristic of atrophic or degenerative tissue. In addition, Cb2 treatment impaired the neoangiogenic process at the morphological level as shown by reduced formation of new blood vessels in endometriotic lesions and at the molecular level by inhibition of VEGF expression. Compared with the controls, there was a significant reduction in the degree of total VEGFR-2 phosphorylation (P < 0.001) in mice treated with Cb2. The investigators believe that these findings, together with previous evidence, support targeting of the angiogenic process through blockade of VEGFR-2 as a potentially successful approach to treatment of peritoneal endometriosis in humans.