Endothelial Nitric Oxide Synthase Gene Polymorphism and Maternal Vascular Adaptation to Pregnancy

Abstract

Abstract-A common polymorphism of the endothelial NO synthase gene that predicts a Glu298Asp amino acid substitution in the mature protein has been associated with cardiovascular disorders in which NO bioactivity is impaired. However, the influence of this polymorphism on endothelial function is unknown. Healthy pregnancy is associated with enhanced endothelium-dependent, flow-mediated dilation (FMD) of the brachial artery, a response mediated by NO. In this study, we investigated the effect of the endothelial NO synthase Glu298Asp polymorphism on endotheliumdependent vasodilation in early pregnancy, making the hypothesis that any genotype-dependent differences in NO generation would be more marked during pregnancy, when the production of NO is upregulated. FMD of the brachial artery was recorded during the first trimester in 139 healthy women with normal singleton pregnancies genotyped for the Glu298Asp variant of endothelial NO synthase. Maternal FMD exhibited a codominant inverse relation with the number of Asp298 alleles (rϭϪ0.21, Pϭ0.01). Among homozygotes for endothelial NO synthase Asp298, FMD (7.99Ϯ1.46%) was significantly lower than that observed among individuals homozygous for endothelial NO synthase Glu298 (10.12Ϯ3.44) (Pϭ0.002). In a backward stepwise multiple regression analysis, vessel size (PϽ0.0001) and Glu298Asp polymorphism (Pϭ0.01) were significantly and independently correlated with FMD. Our findings indicate that the endothelial NO synthase Glu298Asp polymorphism is associated with differences in endothelium-dependent dilation at 12-week gestation and are the first to implicate genetic factors in the normal vascular adaptation to pregnancy. They also provide a potential mechanism linking the endothelial NO synthase polymorphism with the development of cardiovascular disorders and have implications for understanding the genetic basis of preeclampsia. O is an endothelial vasodilator with additional antithrombotic and atheroprotective properties, 1-5 and its deficiency has been implicated in the pathogenesis of hypertension, atherosclerosis, and preeclampsia. 6 -11 Recently, a common Glu298Asp polymorphism of the endothelial NO synthase (eNOS; the enzyme that synthesizes NO in the endothelium) has been associated with the development of these disorders, in which endothelium-dependent vasodilation and NO bioactivity are impaired. [12][13][14][15][16][17] The Asp298 variant has also been shown to be susceptible to enhanced proteolytic cleavage and this might contribute to abnormally low NO generation in carriers of this allele. 18 However, the effects of this variant on endothelial function in human beings are unknown.Normal pregnancy is associated with an increase in blood volume and cardiac output and a fall of blood pressure (BP) in the first half of pregnancy caused by systemic arteriolar vasodilation. 19,20 It has been proposed that the enhanced endothelial synthesis of the NO is responsible for this vasodilation, 21-25 and we and others have shown that flowmediated vasodilation (FMD) of t...

Common Variants of the Endothelial Nitric Oxide Synthase Gene and the Risk of Coronary Heart Disease Among U.S. Diabetic Men

“…Mechanistic studies indicated that this substitution alters function. For instance, associations have been described between this polymorphism and eNOS activity (11,33) or endothelial function (34,35). A mechanism by which eNOS Glu298Asp might reduce NO bioavailability has also been reported.…”

Polymorphisms in the endothelial nitric oxide synthase gene associated with recurrent miscarriage

“…This reduction is reportedly associated with various vascular diseases such as myocardial infarction (Shimasaki et al, 1998), placental abruption (Yoshimura et al, 2001), and pre-eclampsia (Yoshimura et al, 2000;Savvidou et al, 2001). A meta-analysis has revealed a close association between rs1799983 and idiopathic RM (Su et al, 2011).…”

Endothelial NO Synthase Genotype and Risk of Preeclampsia

“…We demonstrated that healthy pregnant women who carried the common Glu298Asp polymorphism in eNOS gene had reduced flow-mediated dilatation of the brachial artery, an NO-dependent response. 33 More recently, we showed that an impairment in the endothelial function is an early feature of women who subsequently developed preeclampsia. 27 Thus, these findings suggest that women homozygous for the Asp298 allele generate low NO in vivo and may be more susceptible to endothelial dysfunction.…”

“…41 The current study supports the hypothesis that endothelial dysfunction attributable to decreased NO bioavailability plays a role in the pathogenesis of preeclampsia. 27,33 …”