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).