Preeclampsia is a serious pregnancy complication threatening the health of mother and fetus and can even cause death. Insufficient trophoblast cell invasion induces incomplete spiral artery remodeling and further leads to hysteroplacental hypoperfusion, which are main pathological manifestations of PE. The pathogenesis of PE may involve multiple pathological changes such as excessive systemic inflammation, oxidative stress, vasospasm, change of cytokines, but is currently unclear.
As an effective vasodilator, NO is involved in the blood pressure regulation of PE, and is activated by three NOSs including neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS). iNOS and eNOS are found in placenta. Unlike the other two NOSs, iNOS can function independently of calcium or calmodulin. The iNOS was found to express on villous mesenchymal cells by iNOS-specific monoclonal antibody. iNOS expression also can be detected in the vascular endothelial cells under the stimulation of inflammation. Uncomplicated pregnancy is itself in the state of oxidative stress, active species superoxide will react with NO to produce peroxynitrite in the development of PE. iNOS can produce NO, thus involve the process of oxidative stress, which may be related to the occurrence of PE. Moreover, pregnancy itself will increase the expression of iNOS in smooth muscle cells, suggesting iNOS may be related to the regulation of uterine muscle tone . iNOS expression is related to the release of free radicals and cytokines involved in PE [25, 26]. Under the condition of inflammatory, iNOS may active more NO and be involve in the pathological process of PE. Besides, iNOS is concerned with the regulation of adaptive changes in renal hemodynamics during pregnancy, which may induce the increased blood pressure in PE. Du et.al suggested enhancive iNOS may facilitate endoplasmic reticulum stress that promoted apoptosis of placenta trophoblast cells in PE. Mazzant et.al  reported that the level of iNOS presented an evident increase in 30 women in a PE group compared with 30 healthy pregnant women. Besides, Mao et.al found that apoE- rat and apoE-/iNOS- rat have an obvious increase in blood pressure compared with wild type (WT). What’s more, the increase in blood pressure in the apoE-/iNOS- rat is higher than the apoE- rat, indicating iNOS may be involved in the pathogenesis of PE related to dyslipidemia.
The onset of PE is regulated by multiple genes, and the SNPs (single nucleotide polymorphisms)s of candidate genes were closely related to susceptibility of PE. Some SNPs of candidate genes related to oxidative stress such as XRCC1, CypA, SOD2 and others showed a statistically significant association with PE[30-32], among them, the polymorphisms of NOS2 play an important role in the development of PE. BHATNAGAR et.al found G300A located in exon 8 and G274T in exon 16 of NOS2 were associated with the occurrence of PE in the population of North India. However, NOS2 rs2779249(-1026C/A) could enhance transcriptional activity of the iNOS promoter and further promote the production of NO, although no obvious difference was found in this polymorphism between PE patients and healthy pregnancy women. Therefore, we analyzed the rs2297518 polymorphism, located in the exon 6 of NOS2 in chromosome 17, that causes an amino acid substitution from serine to leucine and an increase in NOS2 activity, and even alters the NOS2 protein function. Previous studies have shown this polymorphism could affect the susceptibility to many disease conditions, such as inflammatory bowel disease, migraine with aura and so on. Bhatnagar et al. analyzed the polymorphisms of the NOS2 were associated with hypertensive disorders of pregnancy(HDP), especially with PE. Amaral analyzed the genotypes and alleles frequency of NOS2 rs2297518 in 212 healthy pregnant women and 187 PE patients of Brazil population, and found that the GA allele frequency and A allele frequency expresses an obvious increase in PE group. However, a Finland cohort study found no obvious relationship between rs2297518 and the occurrence of hypertension. In our study, we explored the relevance between PE susceptibility and NOS2 rs2297518 from 979 PE patients and 1187 normal pregnant women in Chinese Han population, indicating that there were no significant differences in genotypic and allelic frequencies of this SNP between PE and control groups. To further understand the relationship between NOS2 and PE, we divided the PE patients into mild/severe and early/late-onset groups, the results showed that there were also no significant differences in genetic distributions at the polymorphic sites between mild/severe PE and control groups, or between early/late-onset PE and control groups. These data suggested that the rs2297518 in NOS2 may not play a pivotal role in the pathophysiology of PE in Chinese Han women. This study was the first to explore the relevance between NOS2 rs2297518 and susceptibility of PE in the Chinese Han women.
In conclusion, our results showed that the rs2297518 polymorphism in NOS2 was not associated with PE in Chinese Han women. Even though PE is a complex polygenetic hereditary disease and our research involves large-scale clinical data, the results may be influenced by the multiple races and regions, which need to expand the sample size in a future study. In addition, we only explored the rs2297518 polymorphism in NOS2 but did not analyze the interaction with other polymorphisms. Therefore, genetic studies in other candidate genes for PE from different races and regions are required to detect the possibly different pathophysiological mechanisms, which will increase our understanding of the pathogenesis of PE and further to explore methods of targeted therapy relating to gene changes between populations.