Article

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: 7.63). 05/2012; 60(2):507-11. DOI: 10.1161/HYPERTENSIONAHA.112.194845
Source: PubMed
Download full-text

Full-text

Available from: Eric M George, Aug 21, 2014
2 Followers
 · 
93 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Angiogenesis inhibition by blocking vascular endothelial growth factor (VEGF)-mediated signalling with monoclonal antibodies or tyrosine kinase inhibitors has become an established treatment of various forms of cancer. This treatment is frequently associated with the development of hypertension and proteinuria. As VEGF increases the expression and the activity of nitric oxide synthase in endothelial cells, a decrease in the bioavailability of nitric oxide has been proposed as a key mechanism leading to hypertension during angiogenesis inhibition. However, results of clinical and experimental studies exploring this possibility are conflicting. Rarefaction, that is a structural decrease of microcirculatory vessels, has been reported during antiangiogenic treatment, but evidence that it plays a role in development of hypertension is lacking. Elevated circulating and urinary levels of endothelin-1 have been observed in clinical and experimental studies with angiogenesis inhibitors. Furthermore, the observation that endothelin receptor blockers can prevent or revert the rise in blood pressure during angiogenesis inhibition and attenuate proteinuria provides strong evidence that an activated endothelin-signalling pathway is a final common mediator of angiogenesis inhibition-induced rise in blood pressure and renal toxicity.
    Journal of Hypertension 12/2012; 31(3). DOI:10.1097/HJH.0b013e32835c1d1b · 4.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: INTRODUCTION: Administration of dexamethasone to HELLP syndrome patients (10mg i.v. every 12hours) shortens disease course and reduces maternal morbidity, in patients treated at the University of Mississippi Medical Center (UMMC), associated with this severe form of preeclampsia. However, the pathophysiologic mechanisms involved with this intervention remain unclear. OBJECTIVE: We sought to investigate the potential role of i.v. dexamethasone to restore the imbalance among anti-angiogenic and inflammatory factors known to be significantly elevated in women with HELLP syndrome. STUDY DESIGN: Single center prospective study of women diagnosed with HELLP syndrome that were treated for i.v. dexamethasone at UMMC. Blood was drawn prior to dexamethasone administration and again 12 and 24hrs post initial dexamethasone administration. Enzyme linked immune assays were used to measure circulating inflammatory cytokines and anti-angiogenic factors. Repeated measures ANOVA was used to analyze the data collected before, after and during dexamethasone administration. RESULTS: 17 women with HELLP syndrome were enrolled in this study. Dexamethasone significantly decreased evidence of hemolysis (p=0.002) and liver enzymes (p=0.003), while significantly increasing platelets (p=0.0001) within 24hrs of administration. Circulating IL-6 levels after 24hrs were decreased (p<0.001); sFlt-1 and sEndoglin were also significantly decreased by 24hrs post dexamethasone administration (p<0.002, p<0.004). There were no significant differences in circulating levels of PlGF (p=0.886) due to dexamethasone administration. AT1- autoantibody levels were unchanged by dexamethasone administration. CONCLUSION: We conclude that one important mechanism of dexamethasone administration is to blunt the release of both anti-angiogenic and inflammatory factors suggested to play role in the pathophysiology of HELLP syndrome.
    American journal of obstetrics and gynecology 02/2013; 208(5). DOI:10.1016/j.ajog.2013.01.049 · 3.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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; DOI:10.3109/14767058.2013.784256 · 1.21 Impact Factor