The role of nitric oxide (NO) induced by ROS
Oxygen free radicals have the ability to induce nitric oxide. Different studies show that No has different effects on implantation and ovarian function(17). Harmful effects on sperm motility, toxicity to embryos, and inhibition of implantation can be expected from high NO levels(18, 19). As a free radical agent, No has a significant role in regulating apoptosis(20). Additionally, the enhancement of activity and number of macrophages is related to releasing more cytokines and other immune mediators, such as NO. For the first time, it was reported that NO enhancement is accompanied by the augmentation of activity and the number of macrophages in low-grade inflammation(21). mRNA expression of nitric oxide synthase (NOS) in the epithelial glands of the human endometrium is periodic. The level of NO and NOS in the endometrium of endometriosis’ patients are higher than the endometrium of ordinary women(22-24).
A study has reported the higher NOS activity of peritoneal macrophages, higher peritoneal fluid NO levels, and higher protein expression of peritoneal macrophage inducible NOS in infertile women with endometriosis. This study shows that peritoneal macrophages produce more NO in response to immune stimulation in vitro express higher levels of NOS. Moreover, this kind of macrophage has more NOS enzyme activity. Additionally, enhancement of expression of endothelial NOS in the glandular endometrium of patients with endometriosis has been(22, 23). The iNOS isoforms in tissues of patients with endometriosis is also reported(24). There are studies that show abnormal stimulation of endothelial NO synthase can be the result of different cytokines secreted from immune cells, endometrial cells, or macrophages stimulate endothelial NO synthase to release NO(10, 22, 25). This abnormal stimulation can release a high level of NO, resulting in inhibition of implantation(26).
Moreover, during the menstrual cycle of endometriosis’ patients, the expression of endothelial NO synthase in their endometrium will increase(27). NO is an essential molecule for normal reproductive biological processes like sustaining pregnancy at physiological levels(28). According to a hypothesis in endometriosis patients, stimulation of macrophages for releasing NO can be the result of IL-10, which is augmented within earlier stages of endometriosis(29). Three types of NO synthase produce NO from the conversion of L-arginine to L-citrulline. NOS1, neuronal form, NOS2, the inducible form, and NOS3, the endothelial form(30).
The peritoneal macrophages can move to different parts of the female reproductive system, including fallopian tubes in which fertilization happens. Regarding this subject, these macrophages can cause a more significant risk of infertility because of the increased capacity of macrophages for producing NO(31). It has also been reported that in women with endometriosis-associated infertility, peritoneal macrophages express higher NO synthase2. Additionally, they have higher NO-synthase enzyme activity, and they can produce more NO in response to immune stimulation in vitro(32).