Erythropoietin (Epo) regulates hypoxic ventilation …©Institute of Veterinary Physiology Chart 1 Erythropoietin (Epo) regulates hypoxic ventilation by interacting with brainstem

© Institute of Veterinary Physiology Chart 1

Erythropoietin (Epo) regulates hypoxic ventilation by interacting with brainstem and carotid bodies

University of ZürichUniversité Claude Bernard Lyon1


O2

CO2

Diaphragm

Ven

tilat

ion

Breathing:

Carotid body

Brainstem

Cen

tral

nerv

ous

syst

emP

erip

hera

lne

rvou

s sy

stem


Ventilation underHYPOXIA (diminished PpO2)

PaO2


Molecules controlling the ventilation:

Epotarget genes

Hypoxia-activatedMolecules

(HIF-1)

NeurotransmittersAmines

Steroids

(Pascual, 2004)

(Kline, 2002)


Epo Epo expression occurs in:expression occurs in:

brain

testis

lung

kidney

liver

but also in other organs including:


3 “anti” roles of Epo:

anti-apoptotic

anti-cytotoxic

anti-oxidative

(Tann et al 1992; Masuda et al. 1993; Morishita et al 1997; Koshimura et al. 1999; Tanaka et al. 2001)


Epo and Epo receptor (Epo and Epo receptor (EpoREpoR) in brain) in brain

Epo &EpoR

are expressedin the

mammalian andhuman brain

are expressedin the

mammalian andhuman brain

cerebral Epo is induced by hypoxia

cerebral Epo is induced by hypoxia

are expressed by neurons

and astrocytes

are expressed by neurons

and astrocytes


Does brain-derived Epo

play a role in the control of ventilation under

hypoxia?


- Overexpress Epo ONLY in brain (4 x/Wt)- NORMAL Epo in plasma; HB ; Hct

Transgenic Tg21

Normoxiabasal Ve

20 min

Hypoxia 10%O2

20 min

Hypoxia 6%O215

min

15 m

in


Tg21 maintain high ventilation under at 6% hypoxia

∗ ∗ ∗ ∗ ∗

80

105

130

155

180

205

230

VE

(ml/m

in/1

00g)

exposure time (min)

Tg21WT

21% O2 10% O2 6% O2


Tg21 enhance ventilation after chronic hypoxia

• hypoxic chamber• 3 days at 10% O2

basal Ve

20 min

Hypoxia 10%O2

20 min

Hypoxia 6%O2


EpoR is expressed in the resp.areas of the brainstem

Legends:

4V, 4th ventricle; AP, area postrema; NTS, nucleus tractus solitarius; 7n, facial nerve; PBC, Pre-Bötzinguercomplex; NA, nucleus ambiguus; PY, pyramidal decussation; LC, locus ceruleus. Catecholaminergic areas in the medulla oblongata: A1C1 & A2C2 and in the pons: A5 & A6


Chemodenervation is life-threatening in Wtbut not in Tg21

Chemodenervation


Is the Epo impact on ventilation a

neuro-protectivephenomenon?


0

50

100

150

200

1 2

Activated STAT-5 35 kDa-

Perc

ent o

f con

trol

wt tg21

020406080

100120140

1 2

Activated ERK-1 44 kDa-

Perc

ent o

f con

trol

wt tg210

20406080

100120

1 2

Activated ERK-2

42 kDa-

Perc

ent o

f con

trol

wt tg21

0

15

30

45

60

1 2

JAK-2 45 kDa-

wt tg21

Perc

ent o

f con

trol

STAT5

JNK

PKBMAPK

AktERk1 ERk2

020406080

100120

1

46 kDa-

*P

erce

nt o

f con

trol

wt tg21

020406080

100120

1 2

*

62 kDa-

Perc

ent o

f con

trol

wt tg21


Are Catecholamines

involved in the impactof Epo

in ventilation?


Catecholaminergic group cells in the brainstem


WT Tg21

A1C

1A

2C2

A5

A6


pmol

esN

A/20

min

Nor

adre

nalin

e

0

10

20

30 *

Wt Tg

pmol

esD

OPA

/20m

in

pmol

esN

E

TH

act

ivity

NE

con

tent

A2C2 cell group

4

6

8

10

WT Tg21

*

10

15

20

25

WT Tg21

*


does plasma-derived Epo

impact hypoxic ventilation via CB?


TH

ECAICA

CCA

TH

EpoR is expressed in Carotid bodies glomic cells

Epo-REpo-R

ECAICA

CCA

Legends:

TH, tyrosine hydroxilase; Epo-R, erythropoietin receptor; ICA, internal carotid artery; ECA, external carotid artery; CCA, commun carotid artery


Epo injected (i.v.) in Wt mice modulates the hypoxic ventilatory pattern

Injection of Epo (iv)(2000 U/Kg: 50 U/mouse) Wt C57/Bl6

Epo does notcross the BBB

VE = RR x VT


Carotid body slices: Wistar rats (2 wk old)

Epo triplicates the CB evoked response under hypoxia

500 U/Epo

x 3

0 U/Epo

hypoxia

hypoxia

inclusion

slicing

culturingAmperometry

Spain: Lopez-Barneo


Conclusion

Brain-derived Epo (via EpoR in brainstem) and systemic Epo (via EpoR in carotid bodies) modulate ventilation under hypoxia

These results suggest that Epo has crucial role in the fine-tuning of oxygen homeostasis

High altitude dwellers?

Acute and Chronic mountain sickness?

Lance Amstrong…Epo doping?


C Soulage C BecskeiL Ogunshola J VogelT GorrS KellerD Furrer

Acknowledgements

Prof. M GassmannProf. V JosephProf. JM Pequignot


Is the Epo effect on ventilation a selective Is the Epo effect on ventilation a selective action?action?

Epo mediates general integrity to the tissue

retinal protection

brain injury(stroke)spinalcord

injury

heartinfarct

development?

gonads?


Hello, hello,…. how much oxygen do you have over there?

Erythropoietin (Epo) regulates hypoxic ventilation …©Institute of Veterinary Physiology Chart 1 Erythropoietin (Epo) regulates hypoxic ventilation by interacting with brainstem

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