placental transport in pathologic pregnancies
TRANSCRIPT
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Placental Transport in
Pathologic Pregnancies
Gernot Desoye
Clinic of Obstetrics and Gynaecology
Medical University, Graz
Note: for non-commercial purposes only
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Most Common Pregnancy Pathologies
• Diabetes (T1D, T2D, GMD)fetal overweight
• Fetal growth restriction (FGR)fetal underweight
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Body Composition at Delivery
• Fat mass: 12 – 15 %
• Lean body mass: 85 – 88 %
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LGA AGA SGA
Bo
dy
Fat
(%
)
NGTGDMP=0.002 P=0.002
Fetal Body Fat is Increased in GDM Independent of Body Weight
Petersen 1988; Catalano AJOG 2003; Durnwald AJOG 2004
NGT Col 2 Col 3
LGA AGA
Fat
Fre
e M
ass
(g)
P=0.0009 P=0.0008
LGA AGA
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Padoan et al, AJOG 2004
Fetal Body Fat is Reduced in FGR
FGR:Fetal AC < 2 SD
Abnormal Doppler:
A. umbilicalis
A. uterina
Fat mass
Leanbodymass
AGA
FGR
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Fetal Growth
• Fat Free Mass / Lean Body MassGenetics
• Fat MassIntrauterine Environment
Moulton J Biol Chem, 1923Sparks Sem in Perinat, 1989
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Substrates Driving Fetal Fat Growth
• Glucose Insulin
• Lipids
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Placental Transport in Third Trimester
Glucose
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Maternal-Fetal Glucose Relation is Linear
Biol Neonate 10: 227 (1966)
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intervillousspace
fetalblood
ST ECCT
CT
EC
EC
ST
Pathways of Materno-Fetal Transport
Glucose:
* saturable* stereospecific* Na -indep.* GLUT1* mvm:bm ~ 3:1
* [gluc] >[gluc]m f
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GLUT 1 in Term Placentas
Hahn et al, Cell Tiss Res 280, 1995
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GLUT3
Term Placenta
Mol Hum Reprod 2001 7:1173 JCEM 1998 83:4097
GLUT4
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Hyperglycemia in vitro induces GLUT1 translocation in
term human trophoblasts(Hahn et al., Diabetologia 43: 173, 2000)
Hyperglycemia in vitro downregulates glucose uptake
and GLUT1 in human term trophoblasts(Hahn et al., FASEB J 12: 1221, 1998)
Placental Glucose Transportersin vitro Regulation
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external glucose [mM]
0 5 10 15 20 25
rate
[fm
ole
s/s
per
cel
l]
0
10
20
30
40
50 5.5 mmol/l glucose 25 mmol/l glucose
*
*
Hyperglycemia Downregulates Trophoblast Uptake of High Glucose Levels Only
Hahn et al, FASEB J 1998
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D-g
luco
se(m
mol
.min
-1.to
tal p
lace
ntal
wei
ght-1
)
0
50
100
150
200
250
300 Control
Diet Insulin
GDM
Total Transplacental NetTransfer of Glucose Unaltered in GDM
Osmond et al, Diabetologia 2001
Maternal glucose: 8 mM
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Transplacental Glucose Flux
• Depends on the MATERNAL-FETAL concentration gradient
• Is flow limited
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onTransplacental Glucose Flux Depends
Maternal and Fetal Blood Flow
Illsley et al, Trophoblast Res. 2, 535, 1987
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Placental Glucose Transport in FGR
• Maternal-fetal transfer is unaltered(Challis DE et al, Ped Res 47: 309, 2000)
• GLUT1 expression is unaltered(Jansson T et al, JCEM 77: 1554, 1993)
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Placental Transport in Third Trimester
Lipids
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Lipids
Apoproteins
Cholesterol/esters
Triglycerides
Phospholipids
Vitamins
• Free fatty acids
• Lipoproteins
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Fetal Plasma
TAGPhospholipidsSphingolipidsCholesterol
Free fatty acid
Albumin Complex
FABP
Oxidation•Mitochondria•Peroxisome
Lipid resynthesis•TAG•Phospholipids•Sphingolipids•Cholesterol
Free fattyacid
Signal transduction• Gene regulation• Other biologicalactivity
Free fatty acid
MaternalPlasma
FATP
FAT/CD36
FABPpm
Diffusion
Albumin Complex
Albumin Binding Protein
Dissociation
FAT/CD36
FATP
Diffusion
EL Hydrolysis
Lipoprotein
Lipoprotein Receptor
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Maternal circulation
Placenta
Fetal circulation
Placental Lipid Handling
Free fatty acid
Albumin Complex
Albumin Binding Protein
Dissociation
LP Hydrolysis
Lipoprotein
Lipoprotein Receptor
L
I
P
A
S
E
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Triglyceride Lipase Gene Family
---Pancreatic LipasePL
--+/-Hepatic LipaseHL
--+Lipoprotein LipaseLPL
+++++++++Endothelial LipaseEL
ECTTFTlipase
Gauster et al, JCEM 92: 2256-63 (2007)
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EL and LPL Localisation
Gauster et al, JCEM 92:2256 (2007)
EL LPL control
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0.0
0.5
1.0
1.5
2.0
2.5
EL LPL
lipas
e / R
PL
30 m
RN
A c
op
ies
AGAFGR*
*
modified from Gauster et al, JCEM 92: 2256-63 (2007)
EL and LPL Expression is Alteredin FGR Placentas
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Maternal circulation Placenta Fetal circulation
Placental Lipid Handling
Lipo-
ProteinsELHDL
LDL
HDL
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PLTG
Lipid dropletsv
FA &FC pool
lipase
CE-hydrolase
Maternal circulation Placenta Fetal circulation
Pathways of PlacentalLipid Metabolism
SR-BI
HDL
HDL
CE
A-I
A-I
Selective pathway
?
?
?
LDLEndocytic pathway
LDL receptor CEACAT
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LDLR mRNA expression in placenta
0
0,2
0,4
0,6
0,8
1
1,2
Rat
io L
DL
R/L
30 (
no
rmal
ised
)P < 0.05
LDL-R Expression in FGR and GDM
AGA GDMFGR1 2 + 3
Wadsack et al, AmJPhysiol 292: 476 (2007)
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SR-BI Protein in FGR
Rat
io S
RB
-I/ ββ ββ
-act
inp
rote
inex
pr e
ssio
n(n
orm
aliz
ed)
AGA FGR 1 FGR 2+30.0
0.5
1.0
1.5
2.0
2.5 p=0.03
p=0.07
Wadsack et al, AmJPhysiol 292: 476 (2007)
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SR-BI is Upregulated in Diabetes only at Term of Gestation
term of gestation
control T1D
[au
]
0.0
0.5
1.0
1.5
2.0
2.5 p=0.028
first trimester
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
control T1D
[au
]
control GDM
[au
]
0
1
2
3
4 p=0.002
T1D
GDM
Wadsack et al, unpublished
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Placental SR-BI expression levels do not correlate with:
• Gestational age
• Fetal weight• Placental weight• Maternal BMI• Fetal BMI
• HDL
Correlation placental weight vs SR-BI over all groups
y = 0.6812x + 0.8884
R2 = 0.0399
0.00
0.50
1.00
1.50
2.00
2.50
3.00
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8
Placental weight [kg]
SR
-BI
arb
itra
ry u
nit
s
Correlation fetal weight vs SR-BI over all groups
y = 0.0938x + 0.9519
R2 = 0.0287
0.00
0.50
1.00
1.50
2.00
2.50
3.00
0 1 2 3 4 5
Fetal weight [kg]
SR
-BI
arb
itra
ry u
nit
s
Wadsack et al, unpublished
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LDL-receptorrelated receptor
proteinLRP
apo E-binding protein
- APO-E VLDL- Chylomicron remnants
mainly expressed in:
liver, brain and placenta
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n.s.
n.s.n.s.
AGA IUGR GDM1 2 + 3
LRP Expression in FGR and GDM
0.0
0.5
1.0
1.5
2.0
2.5
Rat
io L
RP
/L30
exp
ress
ion
(no
rmal
ized
to K
+)p= 0.03
n.s.
Wadsack et al, AmJPhysiol 292: 476 (2007)
FGR
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Summary
• Transplacental glucose flux is dictated byconcentration gradient and blood flow
• Glucose transport is unaltered in GDM and FGR
• Lipid hydrolysis and uptake into trophoblast arereduced only in severe forms of FGR
• No information available about overall lipidtransport/transfer in FGR and GDM
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Univ. Milano
I. Cetin V. CozziS. Tabano
Med. Univ. Graz
A. BlaschitzM. GausterT. HahnU. HidenI. LangC. Wadsack
Univ. San Pablo, Madrid
E. HerreraH. Ortega
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Thank you !
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Maternal-Fetal Glucose Gradientis Elevated in FGR vs AGA
AGA FGR0
0.2
0.4
0.6
0.8
1
1.2
1.4
mM
1 2 3
*
**
Marconi et al, Obstet Gynecol, 1996
Maternal glucose concentration is unchanged!
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Maternal and Umbilical Cord Glucose in GDM
Radaelli BJOG, 116, 1729 (2009)
mother fetus
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
mm
ol/l
venous arterial
umbilical cordV - A
**
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PLTG
Lipid dropletsv
FC poollipase
CE-hydrolase
Maternal circulation Placenta Fetal circulation
Pathways of PlacentalCholesterol Metabolism
Steroidproducts
SR-BI
HDL
HDL
CE
A-I
A-I
Selective pathway
?
?
?
LDLEndocytic pathway
LDL receptor CEACAT
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LGA AGA SGA
Bo
dy
Fat
(%
)
NGTGDMP=0.002 P=0.002
NGT Col 2 Col 3
LGA AGA
Fat
Fre
e M
ass
(g)
P=0.0009 P=0.0008
Fat and Fat-free Mass
in Offspring of Women with GDM
Petersen 1988; Catalano AJOG 2003; Durnwald AJOG 2004
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LGA AGA SGA
Bo
dy
Fat
(%
)
NGTGDMP=0.002 P=0.002
Fetal Body Fat is Increased in GDM Independent of Body Weight
Petersen 1988; Catalano AJOG 2003; Durnwald AJOG 2004