Placental Transport in Pathologic Pregnancies

Transcription

1 Note: for non-commercial purposes only Placental Transport in Pathologic Pregnancies Gernot Desoye Clinic of Obstetrics and Gynaecology Medical University, Graz

2 Most Common Pregnancy Pathologies Diabetes (T1D, T2D, GMD) fetal overweight Fetal growth restriction (FGR) fetal underweight

3 Body Composition at Delivery Fat mass: % Lean body mass: %

4 Fetal Body Fat is Increased in GDM Independent of Body Weight P=0.002 P=0.002 NGT GDM NGT Col 2 Col 3 P= P= Body Fat (%) Fat Free Mass (g) LGA AGA SGA LGA AGA Petersen 1988; Catalano AJOG 2003; Durnwald AJOG 2004

5 Fetal Body Fat is Reduced in FGR Fat mass Lean body mass AGA FGR FGR: Fetal AC < 2 SD Abnormal Doppler: A. umbilicalis A. uterina Padoan et al, AJOG 2004

6 Fetal Growth Fat Free Mass / Lean Body Mass Genetics Fat Mass Intrauterine Environment Moulton J Biol Chem, 1923 Sparks Sem in Perinat, 1989

7 Substrates Driving Fetal Fat Growth Glucose Insulin Lipids

8 Placental Transport in Third Trimester Glucose

9 Maternal-Fetal Glucose Relation is Linear Biol Neonate 10: 227 (1966)

10 Pathways of Materno-Fetal Transport Glucose: * [gluc] >[gluc] m f CT EC * saturable * stereospecific * Na -indep. * GLUT1 intervillous space ST ST CT EC EC fetal blood * mvm:bm ~ 3:1

11 GLUT 1 in Term Placentas Hahn et al, Cell Tiss Res 280, 1995

12 Term Placenta GLUT3 GLUT4 Mol Hum Reprod :1173 JCEM :4097

13 Placental Glucose Transporters in vitro Regulation Hyperglycemia in vitro downregulates glucose uptake and GLUT1 in human term trophoblasts (Hahn et al., FASEB J 12: 1221, 1998) Hyperglycemia in vitro induces GLUT1 translocation in term human trophoblasts (Hahn et al., Diabetologia 43: 173, 2000)

14 Hyperglycemia Downregulates Trophoblast Uptake of High Glucose Levels Only mmol/l glucose 25 mmol/l glucose * rate [fmoles/s per cell] * external glucose [m M] Hahn et al, FASEB J 1998

15 Total Transplacental Net Transfer of Glucose Unaltered in GDM Osmond et al, Diabetologia 2001 Maternal glucose: 8 mm D-glucose (mmol.min -1.total placental weight -1 ) 300 Control GDM 50 0 Diet Insulin

16 Transplacental Glucose Flux Depends on the MATERNAL-FETAL concentration gradient Is flow limited

17 Transplacental Glucose Flux Depends on Maternal and Fetal Blood Flow Illsley et al, Trophoblast Res. 2, 535, 1987

18 Placental Glucose Transport in FGR GLUT1 expression is unaltered (Jansson T et al, JCEM 77: 1554, 1993) Maternal-fetal transfer is unaltered (Challis DE et al, Ped Res 47: 309, 2000)

19 Placental Transport in Third Trimester Lipids

20 Lipids Free fatty acids Lipoproteins Apoproteins Cholesterol/esters Triglycerides Phospholipids Vitamins

21 Albumin Complex Dissociation Albumin Binding Protein FABPpm Signal transduction Gene regulation Other biological activity FABP Free fatty acid Diffusion FATP FAT/CD36 Free fatty acid Albumin Complex Free fatty acid FATP TAG FAT/CD36 Lipid resynthesis TAG Phospholipids Phospholipids Sphingolipids Cholesterol EL Hydrolysis Diffusion Lipoprotein Receptor Oxidation Mitochondria Peroxisome Sphingolipids Cholesterol Lipoprotein Maternal Plasma Fetal Plasma

22 Placental Lipid Handling Maternal circulation Fetal circulation Albumin Complex Dissociation Free fatty acid LP Hydrolysis Lipoprotein Albumin Binding Protein Lipoprotein Receptor L I P A S E Placenta

23 Triglyceride Lipase Gene Family lipase FT TT EC EL Endothelial Lipase LPL Lipoprotein Lipase HL Hepatic Lipase +/- - - PL Pancreatic Lipase Gauster et al, JCEM 92: (2007)

24 EL and LPL Localisation EL LPL control Gauster et al, JCEM 92:2256 (2007)

25 EL and LPL Expression is Altered in FGR Placentas lipase / RPL30 mrna copies * * AGA FGR 0.0 EL LPL modified from Gauster et al, JCEM 92: (2007)

26 Placental Lipid Handling Maternal circulation Placenta Fetal circulation LDL Lipo- Proteins HDL EL HDL

27 Pathways of Placental Lipid Metabolism Maternal circulation Placenta Fetal circulation Endocytic pathway LDL receptor LDL ACAT CE? A-I HDL Lipid droplets Selective pathway TG PL v lipase FA & FC pool CEhydrolase? A-I HDL SR-BI CE?

28 LDL-R Expression in FGR and GDM Wadsack et al, AmJPhysiol 292: 476 (2007) LDLR mrna expression in placenta 1,2 P < Ratio LDLR/L30 (normalised) 0,8 0,6 0,4 0,2 0 AGA FGR GDM

29 SR-BI Protein in FGR Ratio SRB-I/β-actin protein expression (normalized) p=0.03 p=0.07 AGA FGR 1 FGR 2+3 Wadsack et al, AmJPhysiol 292: 476 (2007)

30 SR-BI is Upregulated in Diabetes only at Term of Gestation first trimester term of gestation p=0.028 [au] [au] T1D 0 control T1D 0.0 control T1D 4 p= [au] 2 GDM 1 Wadsack et al, unpublished 0 control GDM

31 Placental SR-BI expression levels do not correlate with: Gestational age Fetal weight Placental weight Maternal BMI Fetal BMI HDL Wadsack et al, unpublished SR-BI arbitrary units SR-BI arbitrary units Correlation fetal weight vs SR-BI over all groups y = x R 2 = Fetal weight [kg] Correlation placental weight vs SR-BI over all groups 3.00 y = x R 2 = Placental weight [kg]

32 LDL-receptor related receptor protein LRP apo E-binding protein - APO-E VLDL - Chylomicron remnants mainly expressed in: liver, brain and placenta

33 LRP Expression in FGR and GDM Ratio LRP/L30 expression (normalized to K+) p= 0.03 n.s. n.s. n.s. n.s AGA IUGR GDM FGR Wadsack et al, AmJPhysiol 292: 476 (2007)

34 Summary Transplacental glucose flux is dictated by concentration gradient and blood flow Glucose transport is unaltered in GDM and FGR Lipid hydrolysis and uptake into trophoblast are reduced only in severe forms of FGR No information available about overall lipid transport/transfer in FGR and GDM

35 Med. Univ. Graz Univ. Milano A. Blaschitz M. Gauster T. Hahn U. Hiden I. Lang C. Wadsack I. Cetin V. Cozzi S. Tabano Univ. San Pablo, Madrid E. Herrera H. Ortega

36 Thank you!

37 Maternal-Fetal Glucose Gradient is Elevated in FGR vs AGA Maternal glucose concentration is unchanged! mm * ** AGA FGR Marconi et al, Obstet Gynecol, 1996

38 Maternal and Umbilical Cord Glucose in GDM mother fetus * * mmol/l venous arterial umbilical cord Radaelli BJOG, 116, 1729 (2009) V - A

39 Pathways of Placental Cholesterol Metabolism Maternal circulation Placenta Fetal circulation Endocytic pathway LDL receptor LDL ACAT CE Steroid products? A-I HDL Lipid droplets Selective pathway TG PL v lipase CEhydrolase FC pool? A-I HDL SR-BI CE?

40 Fat and Fat-free Mass in Offspring of Women with GDM P=0.002 P=0.002 NGT GDM NGT Col 2 Col 3 P= P= Body Fat (%) Fat Free Mass (g) LGA AGA SGA LGA AGA Petersen 1988; Catalano AJOG 2003; Durnwald AJOG 2004

41 Fetal Body Fat is Increased in GDM Independent of Body Weight P=0.002 P=0.002 NGT GDM Body Fat (%) LGA AGA SGA Petersen 1988; Catalano AJOG 2003; Durnwald AJOG 2004