Asymmetric Dimethylarginine in the Maternal and Fetal Circulation in Preeclampsia

Abstract

Preeclampsia is a leading cause of intrauterine growth restriction and preterm birth. Endothelial dysfunction is the common final pathway leading to clinical signs of preeclampsia including hypertension and proteinuria. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NOS and induces endothelial dysfunction by reversibly inhibiting NO production from L-arginine. The purpose of this study was to investigate maternal and fetal concentrations of ADMA, L-arginine, and symmetric dimethylarginine (SDMA). Women with preeclampsia (n ϭ 47) and controls (n ϭ 51) who gave birth by cesarean section were included in the study. We analyzed the maternal plasma and umbilical vein and artery plasma. We found that not only maternal concentrations of ADMA and SDMA but also L-arginine were significantly higher in women with preeclampsia than in controls. In fetal samples, only SDMA concentrations were higher in the preeclampsia group than in controls. The median ADMA concentration was three times higher in the fetal circulation than in the maternal circulation, but there was no difference between the preeclampsia group and the control group, and the veno-arterious gradient indicated that the placenta was the source of ADMA. (Pediatr Res 66: 411-415, 2009) P reeclampsia is a common pregnancy complication associated with increased risk of preterm birth and fetal growth restriction (1). The exact etiology of preeclampsia is not known, and hence no definitive preventative measures or treatments are available.Endothelial dysfunction is the common final pathway leading to the clinical signs of preeclampsia including hypertension and proteinuria. It is not known to what extent endothelial dysfunction also affects the infant. Increased concentrations of biomarkers for preeclampsia in the maternal circulation are usually not reflected in the infant. Previously, our group has shown that newborns from preeclamptic pregnancies did not differ from those born after uncomplicated pregnancies with respect to circulating biomarkers of inflammation (CRP and calprotectin) (2), and oxidative stress (3), but newborns from preeclamptic pregnancies had elevated concentrations of homocysteine (4).In women with previous preeclampsia, there is an increased risk for cardiovascular disease later in life (5) and an increased risk of hypertension has also been found for their offspring (6,7).It is not clear whether the increased risk in the offspring is caused by the intrauterine environment, shared genes, or impaired intrauterine growth. In epidemiologic and animal studies, low birth weight by itself is associated with an increased risk of cardiovascular disease and metabolic syndrome (8).NO is essential for vascular tone and endothelial function, and elevated circulating concentrations of asymmetric dimethylarginine (ADMA) are associated with reduced vasodilation and endothelial dysfunction (9). ADMA is an endogenous inhibitor of NOS and induces endothelial dysfunction by reversibly inhibiting NO production from L-arginine. The ratio...

Maternal Vascular Adaptation in High-Risk Pregnancies: Effects of Early Smoking Cessation on Hemodynamic and Endothelial Function

“…We found progressive increases in the ADMA, blood pressure parameters, and heart rate throughout gestation in the overall high-risk cohort, which is consistent with endothelial dysfunction and accumulating cardiovascular strain. These results are consistent with earlier studies showing that elevated ADMA levels during pregnancy are a sign of endothelial stress [ 20 , 22 ]. On the other hand, the cfPWV stayed constant during pregnancy, indicating a preserved arterial compliance, which could be the result of compensatory mechanisms, like an increased cardiac output or systemic vasodilation [ 25 , 26 ].…”

Maternal Vascular Adaptation in High-Risk Pregnancies: Effects of Early Smoking Cessation on Hemodynamic and Endothelial Function

“…We found progressive increases in the ADMA, blood pressure parameters, and heart rate throughout gestation in the overall high-risk cohort, which is consistent with endothelial dysfunction and accumulating cardiovascular strain. These results are consistent with earlier studies showing that elevated ADMA levels during pregnancy are a sign of endothelial stress [ 20 , 22 ]. On the other hand, the cfPWV stayed constant during pregnancy, indicating a preserved arterial compliance, which could be the result of compensatory mechanisms, like an increased cardiac output or systemic vasodilation [ 25 , 26 ].…”

Elevated Plasma Level of Arginine and Its Metabolites at Labor Among Women With Preeclampsia: A Prospective Cohort Study

“…Preeclamptic pregnancy is a state of exaggerated inflammation compared with normotensive pregnancy. 10 , 21 , 22 There are few studies about dimethylarginines in pregnancy complicated by preeclampsia, 3 , 4 , 23–27 and in one of them, similar to the findings of other studies, we showed that women with preeclampsia, at gestational week 35, had higher plasma levels of dimethylarginines than normotensive pregnancy. 4 Normotensive pregnancy, at the beginning, is associated with lower levels of dimethylarginines than nonpregnant women, to facilitate NO`s effect on the cardiovascular system, e.g., decrease blood pressure through decrease resistance and dilatation of vessels.…”

Nitric Oxide and Carbon Monoxide Production and Metabolism in Preeclampsia

“…Symmetric dimethylarginine is renally cleared; potentially, its clearance is compromised in preeclampsia and therefore its levels are not proportionally different than those of ADMA. 10 Our data support the theory that abnormal CO production by HO-1 at the level of the placenta plays a role in the development of preeclampsia. We recognize that data from previous studies of this pathway have been particularly contradictory, which may be in part due to the variability in patient population, laboratory methods, or severity of disease.…”

“…The importance of time in the possible degradation of the enzymes of interest in the frozen specimens is unclear. This, and the fact that the ADMA and SDMA findings are not consistent with most previous studies, 3,5–11 lead us to believe that the ADMA and SDMA results should be viewed with caution and that the findings regarding DDAH-I and DDAH-II are valid and important. This is further supported by the finding of decreased placental NO concentrations in the preeclampsia group.…”

Maternal Vascular Adaptation in High-Risk Pregnancies: Effects of Early Smoking Cessation on Hemodynamic and Endothelial Function

“…We found progressive increases in the ADMA, blood pressure parameters, and heart rate throughout gestation in the overall high-risk cohort, which is consistent with endothelial dysfunction and accumulating cardiovascular strain. These results are consistent with earlier studies showing that elevated ADMA levels during pregnancy are a sign of endothelial stress [ 20 , 22 ]. On the other hand, the cfPWV stayed constant during pregnancy, indicating a preserved arterial compliance, which could be the result of compensatory mechanisms, like an increased cardiac output or systemic vasodilation [ 25 , 26 ].…”

Elevated Plasma Level of Arginine and Its Metabolites at Labor Among Women With Preeclampsia: A Prospective Cohort Study

“…Preeclamptic pregnancy is a state of exaggerated inflammation compared with normotensive pregnancy. 10 , 21 , 22 There are few studies about dimethylarginines in pregnancy complicated by preeclampsia, 3 , 4 , 23–27 and in one of them, similar to the findings of other studies, we showed that women with preeclampsia, at gestational week 35, had higher plasma levels of dimethylarginines than normotensive pregnancy. 4 Normotensive pregnancy, at the beginning, is associated with lower levels of dimethylarginines than nonpregnant women, to facilitate NO`s effect on the cardiovascular system, e.g., decrease blood pressure through decrease resistance and dilatation of vessels.…”

Nitric Oxide and Carbon Monoxide Production and Metabolism in Preeclampsia

“…Symmetric dimethylarginine is renally cleared; potentially, its clearance is compromised in preeclampsia and therefore its levels are not proportionally different than those of ADMA. 10 Our data support the theory that abnormal CO production by HO-1 at the level of the placenta plays a role in the development of preeclampsia. We recognize that data from previous studies of this pathway have been particularly contradictory, which may be in part due to the variability in patient population, laboratory methods, or severity of disease.…”

“…The importance of time in the possible degradation of the enzymes of interest in the frozen specimens is unclear. This, and the fact that the ADMA and SDMA findings are not consistent with most previous studies, 3,5–11 lead us to believe that the ADMA and SDMA results should be viewed with caution and that the findings regarding DDAH-I and DDAH-II are valid and important. This is further supported by the finding of decreased placental NO concentrations in the preeclampsia group.…”

Maternal Vascular Adaptation in High-Risk Pregnancies: Effects of Early Smoking Cessation on Hemodynamic and Endothelial Function

“…We found progressive increases in the ADMA, blood pressure parameters, and heart rate throughout gestation in the overall high-risk cohort, which is consistent with endothelial dysfunction and accumulating cardiovascular strain. These results are consistent with earlier studies showing that elevated ADMA levels during pregnancy are a sign of endothelial stress [ 20 , 22 ]. On the other hand, the cfPWV stayed constant during pregnancy, indicating a preserved arterial compliance, which could be the result of compensatory mechanisms, like an increased cardiac output or systemic vasodilation [ 25 , 26 ].…”

Elevated Plasma Level of Arginine and Its Metabolites at Labor Among Women With Preeclampsia: A Prospective Cohort Study

“…Preeclamptic pregnancy is a state of exaggerated inflammation compared with normotensive pregnancy. 10 , 21 , 22 There are few studies about dimethylarginines in pregnancy complicated by preeclampsia, 3 , 4 , 23–27 and in one of them, similar to the findings of other studies, we showed that women with preeclampsia, at gestational week 35, had higher plasma levels of dimethylarginines than normotensive pregnancy. 4 Normotensive pregnancy, at the beginning, is associated with lower levels of dimethylarginines than nonpregnant women, to facilitate NO`s effect on the cardiovascular system, e.g., decrease blood pressure through decrease resistance and dilatation of vessels.…”

Nitric Oxide and Carbon Monoxide Production and Metabolism in Preeclampsia

“…Symmetric dimethylarginine is renally cleared; potentially, its clearance is compromised in preeclampsia and therefore its levels are not proportionally different than those of ADMA. 10 Our data support the theory that abnormal CO production by HO-1 at the level of the placenta plays a role in the development of preeclampsia. We recognize that data from previous studies of this pathway have been particularly contradictory, which may be in part due to the variability in patient population, laboratory methods, or severity of disease.…”

“…The importance of time in the possible degradation of the enzymes of interest in the frozen specimens is unclear. This, and the fact that the ADMA and SDMA findings are not consistent with most previous studies, 3,5–11 lead us to believe that the ADMA and SDMA results should be viewed with caution and that the findings regarding DDAH-I and DDAH-II are valid and important. This is further supported by the finding of decreased placental NO concentrations in the preeclampsia group.…”