Maternal and Fetal Complications Due to Decreased Nitric Oxide Synthesis during Gestation

*Sonia Jurado, Kaelly Saraiva, Cauane Marceliano, Vanessa Souza and Izabela Vieira* 

## **Abstract**

 Nitric oxide (NO) is synthesized from L-arginine by the constitutive NO synthase in vascular endothelial cells and plays an important role in the regulation of blood pressure and coronary vasomotion. Normal pregnancy is associated with major adaptations in maternal cardiovascular function, which help the woman to accommodate the growing fetus. The vascular endothelium is stimulated during pregnancy to release increased amounts of NO, and the abnormality in the L-arginine NO pathway may play a role in the etiology of preeclampsia. The objective of this study is to discuss the importance of nitric oxide during gestation and the maternal and fetal complications associated with decreased NO synthesis during this period. Maternal arterial hypertension due to inhibition of nitric oxide synthesis during pregnancy impairs fetal development, mainly the reduction of the wall/lumen ratio of the cardiac and renal microvasculature as well as the reduction in the number of nephrons. These changes may contribute to the development of hypertension. Despite these findings, more studies are needed to understand the programming of fetal development, and the intrauterine environmental factors. influence this process.

**Keywords:** nitric oxide, pregnancy, preeclampsia, growth fetal, intrauterine environment

## **1. Introduction**

Normal pregnancy is associated with intensive changes in the maternal cardiovascular system that enables adequate oxygen delivery and nutritive ingredients to the fetus. Physiological vascular adaptation (increased blood volume, increased cardiac minute volume, and reduced vascular resistance) is followed by increased endogenous production of nitric oxide (NO) and improved response of smooth muscles on the reaction of NO [1].

Nitric oxide is synthesized from L-arginine by the constitutive NO synthase in vascular endothelial cells and plays an important role in the regulation of blood pressure and coronary vasomotion. Abnormalities in its production and/or bioavailability are related to diseases such as hypertension, atherosclerosis, and disorders associated with angiogenesis [2].

### *Complications of Pregnancy*

 In normal pregnancy, there is an increase in blood volume and maternal cardiac output, although a decrease in systemic blood pressure occurs. In addition, the responsiveness to various vasoconstrictors is attenuated. This is due to the contribution of nitric oxide (NO) to the vasodilatory phenomena of pregnancy [3].

Nitric oxide is a potent vasodilator and plays an important role in mild relaxation muscles and helps in the vasodilation of maternal blood flow. NO is derived from the amino acid L-arginine, which is in the proteins of all life forms. It is classified as a semi-essential or conditionally essential amino acid [4]. In addition to nitric oxide, other chemical mediators have been implicated in this phenomenon, including estradiol and prostacyclin [5].

 Serum NO concentration of the healthy pregnant women was significantly higher during the second and the third trimester of pregnancy in relation to control nonpregnant subjects [1]. Thus, increased production of nitric oxide by the endothelium contributes to the hemodynamic changes associated with normal pregnancy; conversely, a reduction in NO signaling has been observed in preeclampsia and in several forms of chronic hypertension [6, 7].

Preeclampsia is considered to be one of the most significant health problems in pregnancy, complicating 6–10% of all gestation over 20 weeks, 14–20% of multiple gestations, and 25% of patients with chronic hypertension and/or chronic renal disease [8, 9]. It is characterized of the symptomatic triad: hypertension (systolic pressure ≥ 140 mmHg and/or diastolic pressure ≥ 90 mmHg), proteinuria, and edema [10, 11]. This disease is one of the leading causes of fetal growth disorders, fetal morbidity and mortality, premature labor, and mother's death [4, 10].

Preeclampsia is a specific condition of gestation that involves the failure of several organs. The increase in blood pressure causes deleterious effects on several systems, especially the vascular, hepatic, renal, and cerebral. The complications observed in these systems may explain the high incidence of fetal and maternal mortality and morbidity, which makes preeclampsia one of the leading causes of maternal death in the world [1, 12].

It is interesting to note that there are some risk factors that increase the probability of a pregnant woman presenting with preeclampsia, such as hypertension and preexisting diabetes mellitus, obesity, and ethnicity [12].

Endothelial cell dysfunction can cause hypertension with its increased production of vasoconstrictor agents such as plasma endothelin or reduced release of vasodilator agents such as prostacyclin and NO [13].

Nitric oxide has been proposed as the physiological agent involved in this mechanism as it regulates feto-placental vascular permeability and resistance and platelet aggregation in the placenta. Maturation and development of the placenta is affected significantly by an epigenetic molecule such as nitric oxide which has been postulated to affect fetal programming and survival [14, 15].

The specific cause of NO increase during normal pregnancy is unknown, but it is suggested that increased shear stress during pregnancy stimulates the activity of the endothelial nitric oxide synthase (eNOS). Specifically in the placenta, the activity of this enzyme is important in the sense that NO synthesized locally maintains low vascular resistance, in addition to attenuating the action of vasoconstrictors [16].

 The role of nitric oxide in the pathogenesis of preeclampsia was studied by Rachel et al. [4] who concluded that the circulating levels of nitrite are decreased in women with preeclampsia. One study showed that supplementation with L-arginine in women with preeclampsia lowered blood pressure through increased synthesis or bioavailability of nitric oxide [17].

 Some studies point to the importance of nitric oxide to the outcome of pregnancy. Nitric oxide levels are altered in the blood serum of women who have had an abortion or ectopic pregnancy. The levels in recurrent abortions are decreased, leading to an increase in myometrial contraction, whereas in ectopic pregnancy levels are higher, leading to decreased uterine tube motility and ectopic implantation [18, 19].
