Linking placental ischemia and hypertension in preeclampsia: role of endothelin 1.

Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216, USA.
Hypertension (Impact Factor: 6.87). 05/2012; 60(2):507-11. DOI: 10.1161/HYPERTENSIONAHA.112.194845
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    ABSTRACT: Abstract Objectives: Angiogenic/anti-angiogenic factors have emerged as one of the promising biomarkers for the prediction of preeclampsia. Since not all patients with preeclampsia can be identified by these analytes, the search for additional biomarkers continues. The soluble form of ST2 (sST2), a protein capable of binding to interleukin (IL)-33 and thus contributing to a Th1-biased immune response, has been reported to be elevated in maternal plasma of women with preeclampsia. The aims of this study were to examine: 1) differences in maternal plasma concentrations of sST2 and IL-33 between women diagnosed with preeclampsia and those having uncomplicated pregnancies; 2) the relationship among women with preeclampsia between sST2, umbilical and uterine artery Doppler velocimetry, and the severity of the disease; and 3) the performance of sST2 and angiogenic/anti-angiogenic factors in identifying patients diagnosed with preeclampsia. Methods: This cross-sectional study included women with preeclampsia (n=106) and women with an uncomplicated pregnancy (n=131). Plasma concentrations of sST2, IL-33, soluble vascular endothelial growth factor receptor (sVEGFR)-1, soluble endoglin (sEng), and placental growth factor (PlGF) were determined by ELISA. Area under the receiver operating characteristic curve (AUC) for the identification of preeclampsia at the time of diagnosis was examined for each analyte. Results: 1) Patients with preeclampsia had a higher mean plasma concentration of sST2 than those with an uncomplicated pregnancy (p<0.0001), while no significant difference in the mean plasma concentration of IL-33 between the two groups was observed; 2) the magnitude of this difference was greater in early- compared to late-onset disease, and in severe compared to mild preeclampsia; 3) sST2 did not correlate with uterine or umbilical artery Doppler velocimetry (p=0.7 and p=1, respectively) among women with preeclampsia; 4) sST2 correlated positively with plasma concentrations of sVEGFR1-1 and sEng (Spearman's Rho 0.72 and 0.63; each p<0.0001), and negatively with PlGF (Spearman's Rho -0.56, p<0.0001); 5) while the AUC achieved by sST2 and angiogenic/anti-angiogenic factors in identifying women with preeclampsia at the time of diagnosis were non-significantly different prior to term (<37 weeks of gestation), thereafter the AUC achieved by sST2 was less than that achieved by angiogenic/anti-angiogenic factors. Conclusions: Preeclampsia is associated with increased maternal plasma concentration of sST2. The findings that sST2 does not correlate with uterine or umbilical artery Doppler velocimetry in women with preeclampsia suggest that elevated maternal plasma sST2 concentrations in preeclampsia are not related to the increased impedance to flow in utero-placental circulation, but, most likely, originate from systemic intravascular inflammation and endothelial dysfunction. The performance of sST2 in identifying preeclampsia at the time of diagnosis prior to 37 weeks of gestation was comparable to that of angiogenic/anti-angiogenic factors. It remains to be elucidated if an elevation of maternal plasma sST2 concentrations in pregnancy is specific to preeclampsia.
    The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 03/2013; · 1.36 Impact Factor
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    ABSTRACT: Abstract Objective: Preeclampsia (PE) can be sub-divided into early- and late-onset phenotypes. The pathogenesis of these two phenotypes has not been elucidated. To gain insight into the mechanisms of disease, the transcriptional profiles of whole blood from women with early- and late-onset PE were examined. Methods: A cross-sectional study was conducted to include women with: i) early-onset PE (diagnosed prior to 34 weeks, n=25); ii) late-onset PE (after 34 weeks, n=47); and iii) uncomplicated pregnancy (n=61). Microarray analysis of mRNA expression in peripheral whole blood was undertaken using Affymetrix microarrays. Differential gene expression was evaluated using a moderated t-test (false discovery rate <0.1 and fold change >1.5), adjusting for maternal white blood cell count and gestational age. Validation by real-time qRT-PCR was performed in a larger sample size [early PE (n=31), late PE (n=72) and controls (n=99)] in all differentially expressed genes. Gene ontology analysis and pathway analysis were performed. Results: i) 43 and 28 genes were differentially expressed in early- and late-onset PE compared to the control group, respectively; ii) qRT-PCR confirmed the microarray results for early and late-onset PE in 77% (33/43) and 71% (20/28) of genes, respectively; iii) 20 genes that are involved in coagulation (SERPINI2), immune regulation (VSIG4, CD24), developmental process (H19) and inflammation (S100A10) were differentially expressed in early-onset PE alone. In contrast, only seven genes that encoded proteins involved in innate immunity (LTF, ELANE) and cell-to-cell recognition in the nervous system (CNTNAP3) were differentially expressed in late-onset PE alone. Thirteen genes that encode proteins involved in host defense (DEFA4, BPI, CTSG, LCN2), tight junctions in blood-brain barrier (EMP1) and liver regeneration (ECT2) were differentially expressed in both early- and late-onset PE. Conclusion: Early- and late-onset PE are characterized by a common signature in the transcriptional profile of whole blood. A small set of genes were differentially regulated in early- and late-onset PE. Future studies of the biological function, expression timetable and protein expression of these genes may provide insight into the pathophysiology of PE.
    Journal of Perinatal Medicine 06/2013; · 1.95 Impact Factor
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    ABSTRACT: Objective: An animal model of hemolysis, elevated liver enzymes, low platelet count (HELLP) was used to determine if T lymphocytes accompany hypertension and increased inflammatory cytokines. Methods: sFlt-1 (4.7 µg/kg/day) and sEndoglin (7 µg/kg/day) were infused into normal pregnant rats (HELLP rats) for 8 days. Results: HELLP was associated with increased mean arterial pressure (p = 0.0001), hemolysis (p = 0.044), elevated liver enzymes (p = 0.027), and reduced platelets (p = 0.035). HELLP rats had increased plasma levels of TNFα (p = 0.039), IL-6 (p = 0.038) and IL-17 (p = 0.04). CD4(+) and CD8(+) T lymphocytes were increased. Conclusion: These data support the hypothesis that T cells are associated with hypertension and inflammation.
    Hypertension in Pregnancy 02/2014; 33(1):41-54. · 0.93 Impact Factor


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