Copper chelation inhibits angiogenesis and modulates the oxidative imbalance in a model of endometriosis

Abstract

Endometriosis (EDT) is an estrogen-dependent disease that affects 5-15% of reproductive-aged women. It is characterized by the growth of endometrial-like tissue outside the uterine cavity and often causes chronic pelvic pain and subfertility. Currently, EDT has no cure, and there is an unmet need for new treatment options. Angiogenesis is essential for the growth of endometriotic implants because it ensures an adequate supply of oxygen and nutrients and the removal of waste products. Elevated copper (Cu) levels have been linked to EDT. Cu is required by many enzymes, some involved in the antioxidant system. In cancer, this metal promotes angiogenesis, tumor progression, and oxidative stress. Therefore, our objective was to evaluate the effect of Cu chelation with ammonium tetrathiomolybdate (TM) on angiogenesis and oxidative stress in endometriotic-like lesions. Sixteen female C57BL/6 mice were divided into two experimental groups: EDT and EDT+TM. The EDT induction was performed by autologous uterine tissue transplantation to the intestinal mesentery. The EDT+TM group received 0.30 mg of TM/day in their drinking water for two weeks from the postoperative 15th day. Bodyweight and hematocrit were periodically monitored. Endometriotic-like lesions were collected one month after the pathology was induced to analyze the expression of angiogenic markers (RTqPCR), the presence of endothelial cells (immunofluorescence), and oxidative stress (spectrophotometric methods). Treatment with TM induced anti-angiogenic effects by decreasing the number of blood vessels (p<0.001), the mRNA expression of Fgf2 and Pdgfb (p<0.05), and the presence of endothelial cells (p<0.001). Besides, it decreased antioxidant activity (SOD and CAT, p<0.05) and increased lipid peroxidation (TBARS, p<0.05). In conclusion, TM acts as an effective anti-angiogenic agent and modulates the oxidative imbalance in EDT. These observations support the study of TM as a possible non-hormonal treatment for EDT.