Maternal Vascular Dysfunction Research Articles

Soluble fms-Like Tyrosine Kinase 1 Is Increased in Preeclampsia But Not in Normotensive Pregnancies with Small-for-Gestational-Age Neonates: Relationship to Circulating Placental Growth Factor

An excess of the soluble receptor, fms-like tyrosine kinase 1 (sFlt-1) may contribute to maternal vascular dysfunction in women with preeclampsia by binding and thereby reducing concentrations of free vascular endothelial growth factor and placental growth factor (PlGF) in the circulation. The putative stimulus for increased sFlt-1 during preeclampsia, placental hypoxia due to poor perfusion, is common to both preeclampsia and idiopathic intrauterine growth restriction. However, the latter condition occurs without maternal vascular disease. We asked whether, as with preeclampsia, sFlt-1 is increased and free PlGF is decreased in villous placenta and maternal serum of normotensive women with small-for-gestational-age (SGA) neonates. This was a case-control study using banked samples. Groups of women with SGA neonates (birth weight centile < 10th) and women with preeclampsia were matched to separate sets of normal pregnancy controls based on gestational age at blood sampling (serum) or gestational age at delivery (placenta). sFlt-1 levels were higher in preeclamptics than controls (serum, P < 0.0001; placental protein, P = 0.03; placental mRNA, P = 0.007) but not increased in SGA pregnancies. PlGF was lower in both preeclampsia (serum, P < 0.0001; placental protein, P = 0.05) and SGA (serum, P = 0.0008; placental protein, P = 0.03) compared with their controls. PlGF in preeclampsia and SGA groups did not differ. These data are consistent with a role for sFlt-1 in the maternal manifestations of preeclampsia. In contrast to preeclampsia, sFlt-1 does not appear to contribute substantially to decreased circulating free PlGF in SGA pregnancies in the absence of a maternal syndrome.

Microarray analysis of gene expression in leukocytes from women with preeclampsia

Altered leukocyte function contributes to the maternal vascular dysfunction in women with preeclampsia (PE). The purpose of this study was to gain insight of gene profiles in leukocytes in PE. Venous blood was obtained from women with PE (n = 4) between 31-34 weeks of gestation before delivery. Leukocytes were isolated. Total RNA was extracted and biotin-labeled cRNA was synthesized. cRNA samples were hybridized to the Affymetrix U133A human microarray chip. Results were analyzed using Data mining tool to identify gene transcripts and Microarray Suite for statistical analysis by t-test and P < .05 was set as statistically significant. Ontology analysis was performed using Spotfire computer software. Transcripts were identified as “present” or “absent” in all 4 samples (two were African Americans (AA) and two were Caucasians (C). Among the 22283 known genes, a total of 7089 (32%) transcripts were present in all 4 samples. 7926 (35.5%) transcripts were present only in the AA group and 7430 (33.3%) transcripts were present only in the C group. Expression profiles of the known genes revealed 17 transcripts identified with more than 2-fold increase in the AA group compared to that in the C group, P < .05. In contrast, 13 transcripts were identified with more than 2-fold increase in the C group compared to that in the AA group, P < .05. Based on ontology analysis, significant patterns of gene clusters that are involved in physiological process and cellular process were identified either increased in the AA group or increased in the C group. Specific functional related gene changes include: responses to stress (9 genes), external stimulus (10 genes), cellular defense (4 genes), inflammatory (2 genes), innate immune response (2 genes), and genes related to antigen and MHC protein binding (3 genes). Significant gene profile changes that relate to stress, defense and immune responses were identified in leukocytes in PE. These findings represent the first step towards the identification of altered leukocyte gene expression during PE.

Uterine artery function in pregnant rats fed a diet supplemented with animal lard.

We hypothesised that maternal uterine artery vascular dysfunction could contribute to cardiovascular dysfunction in offspring of rats fed a diet rich in fat. Sprague-Dawley rats were fed for 10 days prior to pregnancy and throughout gestation either: (a) a control breeding diet, or (b) the same diet supplemented with 20 % w/w lard, vitamins, essential micronutrients and protein to control values. At 20 days gestation vascular function was assessed in uterine arteries and third-order mesenteric arteries. Vascular reactivity in response to application of potassium, noradrenaline, the thromboxane analogue U46619, acetylcholine and nitric oxide was assessed. Maternal plasma concentrations of factors likely to contribute to endothelial dysfunction were measured. Maximum acetylcholine-induced relaxation was impaired in the mesenteric arteries of the lard-fed dams (max % relaxation: lard-fed, 69.7 +/- 6.48; control, 85.37 +/- 2.69, P = 0.03). Uterine artery vascular function was similar in the two groups (max % acetylcholine-induced relaxation: lard-fed, 73.7 +/- 4.01; control, 77.5 +/- 4.72, P = 0.98). Concentrations of plasma lipids, 8-epi-PGF(2alpha) and leptin were normal, whereas insulin and corticosterone concentrations were raised in the lard-fed group (insulin (ng ml(-1)): lard-fed, 8.04 +/- 0.47; control, 1.35 +/- 0.37, P < 0.0001; corticosterone (ng ml(-1)): lard-fed, 1164.0 +/- 170.9; control, 541.9 +/- 96.3, P = 0.005). Fetal and placental weights were reduced in lard-fed dams (fetus (g): lard-fed, 4.27 +/- 0.38; control, 2.96 +/- 0.40, P = 0.025; placenta (g): lard-fed, 0.72 +/- 0.06; control, 0.57 +/- 0.04, P = 0.05). Cardiovascular dysfunction in offspring is not associated with reduced uterine artery endothelial function but is associated with activation of the hypothalamic-pituitary-adrenal axis, hyperinsulinaemia and fetoplacental growth retardation.

Elevated level of free 8-iso-prostaglandin F2α in the decidua basalis of women with preeclampsia

Objectives: The prostaglandinlike compound 8-iso-prostaglandin F 2α represents an index of oxidative stress and has the ability to induce endothelial derangement, platelet activation, and vasoconstriction. In women with preeclampsia the decidual spiral arteries contain lipid deposits (acute atherosis). Analogously to the elevated level of 8-iso-prostaglandin F 2α demonstrated in atherosclerotic lesions, we hypothesized that 8-iso-prostaglandin F 2α level would be elevated in preeclamptic decidua basalis tissues. Study Design: Decidua basalis tissues were obtained by vacuum aspiration and placental tissues were obtained by excision at cesarean delivery from 16 preeclamptic and 15 normal pregnancies. Total and free 8-iso-prostaglandin F 2α concentrations were quantified with an enzyme immunoassay technique after lipid extraction and separation. Results: The content of free 8-iso-prostaglandin F 2α in preeclamptic decidual tissues was found to be significantly elevated with respect to that in control tissues. The content of total 8-iso-prostaglandin F 2α did not differ significantly between the groups in either placenta or decidua basalis. Conclusions: We propose that free 8-iso-prostaglandin F 2α released from the decidua basalis in preeclampsia may mediate maternal vascular dysfunction and platelet activation. (Am J Obstet Gynecol 1999;181:1211-5.)

Shedding of syncytiotrophoblast microvilli into the maternal circulation in pre-eclamptic pregnancies.

To investigate whether syncytiotrophoblast microvilli (STBM) are shed into the maternal circulation in increased amounts in pre-eclamptic pregnancies as a possible cause of maternal vascular endothelial dysfunction. A time-resolved fluoroimmunoassay was developed to measure STBM levels in peripheral and uterine venous plasma from normal pregnant and pre-eclamptic women. Three colour flow cytometry was used to assess the microparticulate nature of the STBM in pregnancy plasma. The effects of these plasmas on endothelial cell proliferation was compared and a correlation with the levels of STBM detected was sought. A laboratory investigation using clinical samples obtained from an obstetric practice in a teaching hospital. Peripheral venous plasma from 20 women with established pre-eclampsia, 20 normal pregnant women matched for age, gestation and parity, and 10 nonpregnant women of reproductive age. Paired uterine and peripheral venous plasma taken at caesarean section from 10 women with pre-eclampsia and 10 unmatched normal pregnant women. STBM were detected in the plasma of pregnant women by both flow cytometry and time-resolved fluoroimmunoassay. Significantly higher levels of STBM were found in women with established pre-eclampsia (P=0.01). STBM concentrations were higher in uterine venous plasma than in concurrently sampled peripheral venous plasma, confirming their placental origin. A significant correlation was found between the amount of STBM in the plasma and endothelial cell inhibitory activity. STBM are shed into the maternal circulation (microvillous deportation) and are present in significantly increased amounts in pre-eclamptic women. They may contribute to the endothelial dysfunction underlying the maternal syndrome of pre-eclampsia.

Human placental syncytiotrophoblast microvillous membranes impair maternal vascular endothelial function.

To investigate the hypothesis that, should there be an increase in deported syncytiotrophoblast microvillous membrane fragments in pre-eclampsia, it may cause maternal vascular endothelial dysfunction. Syncytiotrophoblast microvillous membrane (STBM) vesicles, prepared from normal term placentae, were perfused through small subcutaneous arteries isolated from fat biopsies obtained at caesarean section. Endothelial function of these arteries was studied by determining acetylcholine-induced relaxation after preconstriction with noradrenaline. As controls, physiological buffer or red blood cell membranes in physiological buffer were used and endothelial function similarly estimated. Transmission electron microscopy was performed on arteries after perfusion. STBM vesicles, isolated from the placentae of three healthy women undergoing elective caesarean section for reasons unrelated to pre-eclampsia, were suspended in physiological buffer. Subcutaneous fat arteries were obtained from a separate group of 13 normotensive pregnant women, also undergoing elective caesarean section at term. Perfusion with red blood cell membranes or physiological buffer had no significant effect on the concentration dependent relaxation in arteries preconstricted with noradrenaline. However, after 2 h perfusion with STBM vesicles, arteries showed a significant reduction in relaxation to acetylcholine, indicative of altered endothelial function. Transmission electron microscopy of arteries perfused with STBM vesicles confirmed endothelial disruption. STBM vesicle perfusion specifically altered the relaxation response of preconstricted maternal subcutaneous fat arteries to acetylcholine, suggesting an alteration in endothelial dependent relaxation. Deported microvilli may therefore be capable of producing endothelial cell damage and endothelial dysfunction observed in the maternal syndrome of pre-eclampsia.