Placental Transport in

Pathologic Pregnancies

Gernot Desoye

Clinic of Obstetrics and Gynaecology

Medical University, Graz

Note: for non-commercial purposes only

Most Common Pregnancy Pathologies

• Diabetes (T1D, T2D, GMD)fetal overweight

• Fetal growth restriction (FGR)fetal underweight

Body Composition at Delivery

• Fat mass: 12 – 15 %

• Lean body mass: 85 – 88 %

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

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

Fetal Growth

• Fat Free Mass / Lean Body MassGenetics

• Fat MassIntrauterine Environment

Moulton J Biol Chem, 1923Sparks Sem in Perinat, 1989

Substrates Driving Fetal Fat Growth

• Glucose Insulin

• Lipids

Placental Transport in Third Trimester

Glucose

Maternal-Fetal Glucose Relation is Linear

Biol Neonate 10: 227 (1966)

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

GLUT 1 in Term Placentas

Hahn et al, Cell Tiss Res 280, 1995

GLUT3

Term Placenta

Mol Hum Reprod 2001 7:1173 JCEM 1998 83:4097

GLUT4

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

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

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

Transplacental Glucose Flux

• Depends on the MATERNAL-FETAL concentration gradient

• Is flow limited

onTransplacental Glucose Flux Depends

Maternal and Fetal Blood Flow

Illsley et al, Trophoblast Res. 2, 535, 1987

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)

Placental Transport in Third Trimester

Lipids

Lipids

Apoproteins

Cholesterol/esters

Triglycerides

Phospholipids

Vitamins

• Free fatty acids

• Lipoproteins

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

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

Triglyceride Lipase Gene Family

---Pancreatic LipasePL

--+/-Hepatic LipaseHL

--+Lipoprotein LipaseLPL

+++++++++Endothelial LipaseEL

ECTTFTlipase

Gauster et al, JCEM 92: 2256-63 (2007)

EL and LPL Localisation

Gauster et al, JCEM 92:2256 (2007)

EL LPL control

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

Maternal circulation Placenta Fetal circulation

Placental Lipid Handling

Lipo-

ProteinsELHDL

LDL

HDL

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

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)

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)

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

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

LDL-receptorrelated receptor

proteinLRP

apo E-binding protein

- APO-E VLDL- Chylomicron remnants

mainly expressed in:

liver, brain and placenta

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

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

Univ. Milano

I. Cetin V. CozziS. Tabano

Med. Univ. Graz

A. BlaschitzM. GausterT. HahnU. HidenI. LangC. Wadsack

Univ. San Pablo, Madrid

E. HerreraH. Ortega

Thank you !

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!

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

**

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

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

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