Pathogenesis of Preeclampsia

Beek, Erik van; Peeters, L.

doi:10.1097/00006254-199804000-00021

Cited by 101 publications

(31 citation statements)

References 49 publications

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“…10,11,32 This leads to an increase in systemic vascular resistance and sensitivity to pressor agents. [32][33][34] In support of this model, experimental inhibition of NO synthesis in pregnant rats results in the development of sustained hypertension, proteinuria, thrombocytopenia, and intrauterine growth restriction mimicking the human disorder. 35,36 Preeclampsia is known to be heritable, and although the nature and number of predisposing genes are unknown, linkage studies of affected sibling pairs have implicated the eNOS gene locus on chromosome 7q35 to 36.…”

Section: Discussionmentioning

confidence: 80%

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

et al. 2001

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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...

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Section: Discussionmentioning

confidence: 80%

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

et al. 2001

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“…1 It is clinically characterised by an elevated blood pressure and proteinuria. Although the pathogenesis of the disorder is not yet elucidated, it is thought that oxidative stress and damage of the endothelium lining the blood vessel wall are important contributing factors.…”

Section: Introductionmentioning

confidence: 99%

The C242T-polymorphism of the NADPH/NADH oxidase gene p22phox subunit is not associated with pre-eclampsia

et al. 2002

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Pre-eclampsia is a pregnancy-related multisystem disorder characterised by elevation of blood pressure and proteinuria, in which oxidative stress may play an important role. Blood pressure is partly controlled by O − 2 production by NADPH/NADH oxidase and recently it was shown that a C242T substitution in the p22phox gene was associated with coronary artery disease, in which elevated blood pressure and oxidative stress are also important pathophysiologic features. Therefore we studied the prevalence of the C242T polymorphism in the NADPH/NADH oxidase gene in women with preeclampsia and/or haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome as compared with women with a normotensive pregnancy. DNA from control women (n = 78), women with pre-eclampsia (n = 40), HELLP syndrome (n = 9) or women with HELLP compli-

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“…3; Gerretson et al, 1981;Van Beek and Peeters, 1998). PE occurs in an estimated 7-10% of primigravida pregnancies but is unknown in other mammals (Sharkey et al, 2001), with the exception of patas monkeys (Palmer et al, 1979;Ramsay et al, 1997).…”

Section: Trophoblast Migration and Preeclampsiamentioning

confidence: 99%

“…In normal pregnancy these physiological changes appear as far proximally as the myometrial portion of the spiral arteries. In preeclampsia the physiological changes are less dramatic and appear only more distally in the arteries (modified from Van Beek and Peeters, 1998). characterized by shallow penetration of the endometrium and a smaller number of arteries being invaded by EVCs.…”

Section: Trophoblast Migration and Preeclampsiamentioning

confidence: 99%

Human physiological adaptation to pregnancy: Inter‐ and intraspecific perspectives

Rockwell

Vargas

Moore

2003

American J Hum Biol

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Reproductive success requires successful maternal physiological adaptation to pregnancy. An interspecific perspective reveals that the human species has modified features of our haplorhine heritage affecting the uteroplacental circulation. We speculate that such modifications - including early implantation and deep, widespread invasion of fetal (trophoblast cells) into and resultant remodeling of maternal uterine vessels - are responses to or compensation for the biomechanical constraints imposed by bipedalism which, in turn, render our species susceptible to the pregnancy complication of preeclampsia. Preeclampsia is characterized by incomplete remodeling of maternal uterine vessels as the result of shallow trophoblast invasion, which in turn reduces uteroplacental blood flow and frequently leads to intrauterine growth restriction (IUGR). Using an intraspecific perspective, we consider the fitness-related consequences of variation in uteroplacental blood flow during high-altitude pregnancy. Although birth weights are reduced at high altitudes in Bolivia, multigenerational Andean residents are relatively protected from altitude-associated IUGR. Our preliminary data suggest that Andean women have greater uteroplacental oxygen delivery than European high-altitude residents due to more complete growth and remodeling of maternal uterine vessels. Identification of the physiological and genetic mechanisms involved in such inter- and intraspecific variations in pregnancy physiology will likely be useful for understanding human evolution and contemporary challenges to successful reproduction.

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Pathogenesis of Preeclampsia

Cited by 101 publications

References 49 publications

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

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

The C242T-polymorphism of the NADPH/NADH oxidase gene p22phox subunit is not associated with pre-eclampsia

Human physiological adaptation to pregnancy: Inter‐ and intraspecific perspectives

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