Abstract-We tested the hypothesis that endothelial dysfunction could cause placentation-related defects, persist after the complicated pregnancy, and probably cause cardiovascular disease later in life. Brachial arterial reactivity and factors related to endothelial dysfunction, such as circulating cholesterol, uric acid, nitrites, L-arginine, asymmetrical dimethylarginine, vascular endothelial growth factor, and soluble vascular endothelial growth factor receptor-1, in women with previous healthy pregnancies (nϭ22), patients with severe preeclampsia (nϭ25), or patients with recurrent pregnancy loss (nϭ29), at day 10 of the luteal phase of an ovulatory cycle an average of 11 to 27 months after pregnancy were evaluated. Both groups with placentation defects had a significant decrease in endothelium-dependent dilatation, a higher rate of endothelial dysfunction, lower serum nitrites, and higher cholesterol as compared with control subjects; subjects with previous preeclampsia additionally had higher normal blood pressures and a greater parental prevalence of cardiovascular disease. Patients with recurrent pregnancy loss also demonstrated a significantly lower endotheliumindependent vasodilatation. A trend to an inverse correlation was found between serum cholesterol serum and endothelial-mediated vasodilatation in the whole study population. Uric acid, L-arginine, asymmetrical dimethylarginine, vascular endothelial growth factor, and soluble vascular endothelial growth factor receptor-1 were similar in all of the groups. We postulate that endothelial dysfunction may represent a link between preeclampsia and increased cardiovascular disease latter in life and propose that women with unexplained recurrent miscarriages are also at increased cardiovascular risk. The identification and correction of endothelial dysfunction detected during the reproductive stage on obstetric outcome and on cardiovascular diseases needs to be elucidated. Key Words: endothelial dysfunction Ⅲ endothelium-mediated vasodilatation Ⅲ pregnancy Ⅲ preeclampsia Ⅲ recurrent abortion Ⅲ cardiovascular risk P reeclampsia not only elevates obstetric morbidity and mortality, but also places the mother at increased risk for developing cardiovascular disease (CVD) later in life. Indeed, subjects with preeclampsia are susceptible to hypertension, obesity/metabolic syndrome, and to CVD particularly if the preeclampsia is complicated by preterm birth. [1][2][3][4] Interestingly, subjects with recurrent spontaneous abortions have also been reported to be at increased risk for the development of cerebrovascular disease later in life. 5 This suggests that there may be underlying risk factors of CVD that predispose to both preeclampsia and/or spontaneous abortions, 2 conditions that represent different degrees of placentation defects.One potential unifying mechanism could involve the presence of endothelial dysfunction before the obstetric complication. Maternal endothelial dysfunction could impair the invasion of extravillous trophoblasts into the spiral arter...

Noris et al describe that preeclamptic women have decreased placental villi L-arginine concentration and overexpression of arginase II. 1 In February, Alexander et al reported that supplementing L-arginine in pregnant rats with reduced uterine perfusion decreased blood pressure, concomitantly increasing serum L-arginine levels and urinary nitrite/nitrate. 2 Both reports highlight the role of the L-arginine-nitric oxide (NO) pathway in determining normal and preeclamptic pregnancies and sustain the potential benefit of L-arginine supplementation in women at risk of preeclampsia. Although L-arginine has been given acutely to preeclamptic women, there is no concordance about its benefits. 3,4 We wish to underscore the benefits of this intervention with our experience with chronic long-term oral L-arginine supplementation in women at risk of placentation-related disorders.Seventeen women with bilateral notching and high uterine artery resistance in transvaginal ultrasounds performed 2 weeks apart (Ϫ2 and 0 weeks) were included. Endothelial function was also assessed by high-resolution ultrasound of the brachial artery. Of the 15 multiparas, 3 had presented preeclampsia associated with stillbirth in 2, 5 had unexplained recurrent abortions, 2 had isolated spontaneous abortions, and 1 had a premature delivery of ischemic origin. None presented thrombophilias. L-Arginine supplementation (0.1 g/kg per day PO; Smartbasics, San Francisco, Calif) was started at 10.1Ϯ0.9 (SEM) weeks of gestation (week 0), and continued until delivery. After 2 weeks on L-arginine, the women's mean arterial pressure and uterine artery resistance index decreased (75Ϯ2 versus 82Ϯ3 and 80Ϯ2 mm Hg; 0.76Ϯ0.01 versus 0.89Ϯ0.02 and 0.87Ϯ0.01 and at Ϫ2 and 0 weeks respectively; PϽ0.05 for 2 versus 0 and Ϫ2 weeks for both values), and endothelial-mediated vasodilatation improved (10.9%Ϯ1.0% versus 7.7%Ϯ1.9% and 5.5%Ϯ1.2%; PϽ0.05 for 2 versus Ϫ2 weeks). All women delivered at term (38.0Ϯ1.1 week), and excepting 1, had infants of normal weight (3227Ϯ371 g); one woman developed a moderate preeclampsia ( 2 ϭ12.5, PϽ0.001 for the combination of live births, perinatal outcome, and preeclampsia versus the preceding pregnancy). Maternal tolerance to supplementation was adequate; the offsprings presented no side effects at birth or during 2 to 48 months follow-up.Our data show that the acute enhancement of the L-arginine-NO pathway ameliorates the local and systemic adaptations of pregnancy. While the improvement of the perinatal outcome could represent a spontaneous remission, a beneficial effect of L-arginine is suggested, because 9 out of 17 women previously presented 2 or more placentation-related complications of pregnancy, and patients with this clinical history have recurrence rates of preeclampsia or pregnancy loss of 40% to 60%, respectively. Moreover, all women included in this intervention presented in early pregnancy bilateral notching of the uterine arteries, index associated to odds ratio of 42.02, 8.61, and 2.38 for preeclampsia, fetal growth r...