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  • Complex, multisystemic features of preeclampsia Hypertension Proteinuria Eclampsia HELLP syndrome Intra-uterine growth restriction Multi-organ disease Cerebral vessels Fetus Liver Systemic blood vessels Kidneys
  • Oxidative stress Antioxidant capacity ROS synthesis O 2 . _ H 2 O 2 ONOO _ Vitamin C SOD
  • 2-Stage Model of Preeclampsia Maternal constitution : Environment/Behavior/ Genetics -> syndrome X Adaptation to pregnancy Later life endothelial disease (Hypertension, Ischemic heart disease) Oxidative stress Placental events : Abnormal Implantation Placental hypoperfusion Maternal endothelial cell dysfunction Preeclampsia STAGE 1 STAGE 2 Maternal constitution : Environment/Behavior/ Genetics -> syndrome X Oxidative stress Bilodeau and Hubel J Obstet Gynaecol Can 2003;25:742; Roberts and Hubel LANCET 1999; 354:788 View slide
  • Spiral Arteries Non-pregnant Normal Pregnancy View slide
  • Spiral Arteries Normal Pregnancy Preeclampsia
  • Xanthine Oxidase/Dehydrogenase Xanthine Xanthine dehydrogenase (XD) NADH + Uric Acid Xanthine Xanthine oxidase (XO) O 2 .- + Uric Acid Hypoxia Cytokines XD XO Posthypoxic reperfusion: XD XO O 2 .-
  • Xanthine Oxidase/ Dehydrogenase Many, Hubel, Fisher, Roberts, Zhou Am J Pathol 2000 Placental bed curettings
  • OH - R R O N O O ONOO - peroxynitrite + tyrosine nitrotyrosine NO . O 2 .- Nitrotyrosine residues: a “footprint” of ROS/RNS damage
  • Normal, Villous placenta Normal, Invasive cytoytophoblast Preeclampsia, Villous placenta Preeclampsia, Invasive cytotrophoblast Many A et al. 2000 Also reported by Myatt et al. 1996; 1998 Cytokeratin Nitrotyrosine Nitrotyrosine
  • Hung T-H, Skepper JN, Burton GJ. Am J Pathol 2001; 159:1031-1043 Nitrotyrosine Immunoreactivity in Villous Tissues w/wo Hypoxia-Reoxygenation Immediately after delivery After hypoxia (95%N 2 /5%CO 2 ) 2 hrs. Hypoxia 20 min. + 2 hrs. reoxygenation (5%O 2 /90%N 2 /5%CO 2 ) Hypoxia 20 min. + 2 hrs. reoxygenation (air / 5%CO 2 ) Hypoxia 20 min. + 2 hrs. reoxygenation (air / 5%CO 2 ) Negative control
  • cytosol NAD(P)H oxidase Cytochrome b558 Mox NAD(P)H NAD(P)+ H+ rac p67 p47 p22 membrane O 2 ._ O 2 ._ O 2
  • Endothelial mediated relaxation to methacholine is blunted by preeclampsia plasma 0 20 40 60 80 100 % Constriction 1E-09 1E-08 1E-07 1E-06 1E-05 Methacholine Dose (M) Preeclamptic Pregnancy Plasma (n=7) Normal Pregnancy Plasma (n=7) p<0.05 Gandley and Hubel, 2003
  • Endothelial mediated relaxation to methacholine is restored by losartan % Constriction Methacholine Dose (M) p<0.05 (20) (10) 0 10 20 30 40 50 60 70 80 90 100 1E-09 1E-08 1E-07 1E-06 1E-05 Preeclamptic Plasma +Losartan (n=5) Normal Plasma +Losartan (n=5) Preeclamptic Pregnancy Plasma (n=7) Normal Pregnancy Plasma (n=7)
  • Ascorbate is an outstanding antioxidant : • Ascorbate is the “first line” water-soluble antioxidant. • Ascorbate radical, formed from quenching of more powerful oxidants, is unreactive. • Vitamin C regenerates vitamin E (synergistic action). From: Carr AC. Circ Res 2000;87:349
  • Endothelial function: Unique salubrious effects of ascorbate • Intracellular ascorbate (mM) competes effectively with NO . for O 2 .- . • Plasma ascorbate (30-60 µM) inhibits membrane lipid peroxidation and formation of oxLDL. • Preservation of BH 4 cofactor of NOS • Involved in release of NO from S-nitrosothiols From: Carr AC. Circ Res 2000;87:349
  • 0 5 10 15 20 RSNO,nmol/ml Whole plasma Low MW thiols Albumin 9.2 ± 1.6 9.4 ± 1.5 11.1 ± 2.9 * ** S-nitrosothiols are Increased in Predeclampsia Plasma Tyurin, Liu, Tyurina, Sussman, Hubel, Roberts, Taylor, Kagan Circ Res 2001;88:1210-1215. 4.5 ± 1.0 4.4 ± 1.0 4.8 ± 1.2 4 .2 ± 1.0 5.1 ± 0.7 6.3 ± 1.4
  • - Ascorbate + Ascorbate Time, sec 0 200 400 600 20 40 60 80 0 Current, p  Ascorbate,  M Initial rate of NO release, pmol/sec A B Release of NO from S-NO-albumin occurs at relevant ascorbate concentrations 0 40 80 120 3 6 9 12 0
  • The V itamins I n P re-eclampsia Study Chappell et al., Lancet 1999 Analysis: Intention-to-treat Completed study 1512 women screened at 18-22 weeks 242 abnormal & recruited to study 283 randomised 41 women with history of pre-eclampsia 142 assigned placebo 141 assigned 1000mg vitamin C and 400IU vitamin E 81 participated until delivery 79 participated until delivery
  • Clinical outcome 0 5 10 15 20 25 Number of women with pre-eclampsia Intention- to-treat Completed study Placebo Vitamins C and E Adjusted odds ratio: 0.39 (0.17-0.90) p=0.02 0.24 (0.08-0.70) p=0.002 Chappell et al 1999
  • Longitudinal evaluation of indices of oxidative stress in plasma (placebo arm of antioxidant trial)  low-risk group  Preeclampsia developed  Delivered of SGA infants Chappell LC et al. Am J Obstet Gynecol 2002 187:127-36.
  • Risk Factors in Common For Atherosclerosis and Preeclampsia • Hypertension • Diabetes • Collagen vascular disease • Increased plasma homocysteine • Obesity • Insulin resistance syndrome Up to half of patients with coronary artery disease have serum cholesterol concentrations in the normal range…
  • The Atherogenic Lipid Phenotype in women with preeclampsia • Increased triglycerides (TG-rich lipoproteins) • Predominance of small, dense LDL particles • Decreased HDL-cholesterol • Post-prandial lipemia • Increased circulating free fatty acids Underlying factors: insulin resistance and increased human placental lactogen
  • Free fatty acid-mediated conformational changes in albumin increase the redox activity of albumin-associated Cu, converting albumin from an antioxidant to a prooxidant Kagan, Yturin, Borisenko, Fabisiak, Hubel, Ness, Gandley, McLaughlin, Roberts Hypertension Pregn. 2001;20:221-42 Cu 1+ Ascorbate Ascorbate Radical Cu 2+ serum albumin FFA Dehydro-ascorbate -e
  • Vascular Smooth Muscle Interstitial Space Endothelial Cells Protein Damage (nitrotyrosine) ASC ASC GTP Relaxation NAD(P)H Oxidase GC NAD(P)H Oxidase eNOS cGMP Lumen (blood ) ANG II Shear Stress TNF  Oxidized lipids ONOO - ONOO - NO • NO • H 2 0 2 H 2 0 2 H 2 0 ANG II TNF  0 2 •- 0 2 •- 0 2 •- CATALASE [ BH 4 ] + + 0 2 •- + Potential mechanisms of decreased NO bioavailability andaltered vascular function in pre-eclampsia Bilodeau and Hubel, 2003