Effects of female sex hormones on folic acid–induced anti-angiogenesis

Aim: Pregnant women have been recommended to take FA daily to prevent birth defects in the brain and spinal cord. We previously showed that folic acid (FA) exerts an anti-angiogenic activity. As angiogenesis is important for endometrial reorganization and embryonic development, there should be some mechanisms to allow the pregnant mother and the foetus to escape from the FA-induced anti-angiogenesis. This study was designed to investigate the effect of female sex hormones on the FA-induced anti-angiogenic activity. Methods: The protein levels and protein-protein interaction were examined by Western blot analysis and immunoprecipitation assay respectively. The cell proliferation and migration were examined by MTT assay and wound healing assay respectively. The in vivo angiogenesis was evaluated by Matrigel angiogenesis assay. Results: In human umbilical venous endothelial cells (HUVEC), FA receptor (FR) formed a complex with progesterone receptor (PR), oestradiol receptor (ER) and cSrc. Pregnancy levels of progesterone (P4) or oestradiol (E2) prevented FA-induced inhibitions of proliferation and migration in HUVEC. Both E2 and P4 prevented the FA-induced anti-angiogenesis in vivo. Moreover, cotreatment with FA and P4 or E2 inhibited the signalling pathways involved in FA-induced inhibitions of proliferation and migration in HUVEC. Conclusion: Female sex hormones interrupt the FA-induced anti-angiogenic action through receptor-receptor interaction.