Sie sind auf Seite 1von 33

The Neurovascular Unit: Neurovascular Coupling in Health and Disease

Costantino Iadecola, M.D.


Brain and Mind Research Institute Weill Cornell Medical College New York, NY, USA

Mechanisms of Cerebrovascular Regulation

Astrocyte
Endothelium

FUNCTIONAL HYPEREMIA
Synaptic activity

Myocyte/Pericyte

AUTOREGULATION CBF

Functional imaging

Ingvar and Lassen

Arterial pressure Cell Metab 7: 476, 2008

Multiple agents and cells mediate the increase in CBF evoked by activation
Ca++ Glu GJ mGluR Ca++ waves Ca++ Ca++ COX EETs PGs Central pathways/interneurons Glu K+ H+ NO PGs NOS COX-2 Ado ATP

Ado

Arteriole

Astrocytes
ATP

P450 Ado K+ siphoning

NO GABA 5HT NE ACh DA SP NT VIP SOM NPY Brain Lang 102: 141-152, 2007

The brain is vascularized from the outside in

Nat Neurosci Rev 5: 347, 2004

Neurons, glia and vascular cells work in concert to regulate cerebral blood flow
Synaptic activity
Gap junction Smooth muscle


NO

Interneuron

Glia

endothelium

Shear stress

Remote vasodilation

Retrograde vasodilation Flow-mediated vasodilation

Local vasodilation

Pial artery

Arteriole

Capillary

The Neurovascular Unit: Blood flow regulation and beyond


Myocyte/PericyteAging Endothelium

Perivascular cells Hypertension


Cerebral Arteriole

Astrocyte

Alzheimer
Neuron Axon

Flow regulation

BBB exchange

Immune surveillance

Trophic support (vascular niche)


Acta Neuropathol 120:287, 2010

Alzheimers Disease: The Amyloid Hypothesis


Vascular amyloid

A40 Amyloid Plaques

Do vascular factors contribute to the mechanisms of Alzheimers disease?

A peptides

?
Neuronal dysfunction

Vascular dysfunction

Cell. Mol. Neurobiol, 23:681, 2003

Methods to investigate neurovascular regulation in mice


Ringer or Acetylcholine

CBF

Field potentials
MAP mmHg

100 60 130 100

Neocortex

CBF % incr.

CP
Stim.

Thal

Functional hyperemia, endothelium-dependent vasodilatation (acetylcholine, A23187), smooth muscle function (adenosine)

Neural and vascular CBF responses are attenuated in Tg2576 mice at an early age
APP mice (age 3 months)
40 CBF (% increase) 30 Wild Type APP mice 150 100 50 0 -50 50 100 150 200 Mean arterial pressure (mmHg) Niwa et al., AJP 2002; 283:H315 Wild type APP mice

20 * 10 0 *

Whisker Stimulation

Acetylcholine

Iadecola et al., Nat Neurosci 2:157,1999; PNAS 97:9735, 2000

CBF response to adenosine, papaverin and NO donors not affected

CBF (% change)

* p<0.05; n=5/group

-100 0

Vascular dysregulation increases the susceptibility to ischemic injury in Tg2576 mice


Intraischemic CBF Infarct volume

Time after MCA occlusion (min)


*Resting flow: Non-Tg: 1481; Tg: 1059 ml/100g/min
J. Neurosci 76:1755, 1997

AD patients have more cerebrovascular lesions than controls

Jellinger and Mitter-Ferst., J. Neurol 250:1050, 2003

AD patients have more strokes than age-matched controls

NADPH oxidase is a major source of free radicals in cerebral blood vessels in AD models
Tg2576 mice
3-NT

Ligand
NADPH oxidase
NOX p22 p47 Rac1 p67 Serine phosphorylation

O2-

PKC

Cellular dysfunction
JCBFM 24:334, 2004

Developing APP mice deficient in NOX2

Tg2576

NOX2-/-

Tg2576

Tg2576/NOX2-/-

Nox2 deficiency rescues neurovascular dysfunction and behavioral deficits in Tg2576 mice
Young (3-4 months) Old (12-15 months) 20 20

75 50 25

20

75 50 25

20

Time in novel arm (sec)

*
10

*
#

*
#

100

10

10

10

Time in novel arm (sec)

Novel arm entry (%)

Novel arm entry (%)

stimulation Whisker stimulation A100 A100B 30 A 30 A 30Whisker B 30 stimulation


CBF (% increase) CBF (% increase) CBF (% increase) CBF (% increase)

Whisker

Acetylcholine Acetylcholine Cognitive function

B 150 B 150
100

50

50

WT

Nox2-/WT

0 0 0 0 0 0 Tg2576 Tg2576/Nox2-/Tg2576 Tg2576/Nox2-/Nox2-/Tg2576 Tg2576/Nox2-/WT Nox2-/Nox2-/Tg2576 Tg2576/Nox2-/WT Nox2-/Tg2576 Tg2576/Nox2-/WT WTNox2-/Tg2576 Tg2576/Nox2-/WT

WT Nox2

C 30 C 30
CBF (% increase) CBF (% increase)
20 20

Bradykinin Bradykinin

CBF (% increase)

*
10

Tg2576

30 (DHE)

CBF (% increase)

ROS

D 40 D 40
30 20

Adenosine Adenosine

Tg2576/Nox2-/PNAS 105: 1347, 2008 10

*
#

*
#

20 10

10

CD36, an innate immunity receptor, binds A and activates inflammatory signaling


CD3 6
Lipid raft
Vav-GEF

A
NOX p22 p47 Rac1 p67 NADPH oxidase
Serine phosphorylation

NF-B

O2-

Oxidative stress

Nucleus

inflammation

Deletion of CD36 prevents the neurovascular dysfunction and oxidative stress in Tg2576 mice
Tg2576

CD36-/-

Radicals

Tg2576

Tg2576/CD36-/-

PNAS 108: 5063, 2011

CD36 deletion reduces cerebral amyloid angiopathy, but not amyloid plaques

No difference in plaque load

PNAS 110: 3089, 2013

CD36 deletion reduces pericyte damage in tg2576 mice

PNAS 110: 3089, 2013

Is CD36 in perivascular macrophages (PVM) involved in the neurovascular dysfunction of A 1-40?


Brain parenchyma

PERIVASCULAR SPACE
PVM CD36

Vascular oxidative stress


ROS

Nox2 Vascular dysfunction

EC

Cerebral artery SMC

Glia limitans

Bone marrow transplant replaces 80% of perivascular macrophages


Glut-1

CD31/GFP

CD206

50 m

The cerebrovascular dysfunction in tg2576 mice is rescued by transplant of CD36-/- bone marrow
Tg2576 mice

Is CD36 in perivascular macrophages (PVM) involved in the neurovascular dysfunction of A 1-40?


Brain parenchyma

PERIVASCULAR SPACE
PVM CD36

Vascular oxidative stress


ROS

Nox2 Vascular dysfunction

EC

Cerebral artery SMC

Glia limitans

PARP and TRPM2 mediate A induced endothelial dysfunction Ca2+


CD3 6

NADPH oxidase
NOX p22 p47

TRPM2

Vav-GEF

Nu

Rac1 p67

O2-

ADPR

NO

PN
DNA damage

PARG

Ca2+

PAR
PARP

Endothelia l dysfunctio n

A -induced peroxynitrite leads to DNA damage and PARP activation in cerebral endothelial cell cultures

Vehicle

A1-40

A activates endothelial TRPM2 channels in a PARP/PARG- dependent manner, leading to Ca2+ overload and NO suppression
Ca2+ overload

NO (DAF-FM)

Peroxynitrite is involved in A -induced endothelial dysfunction in vivo

p<
Acetylcholine *p<0.05 N=10/group

PARP activity and TRPM2 channels are required for A -induced endothelial dysfunction in vivo
Acetylcholine

PARP1-/- mice

tg2576

PARP and TRPM2 mediate A induced endothelial dysfunction Ca2+


CD3 6

NADPH oxidase
NOX p22 p47

TRPM2

Vav-GEF

Nu

Rac1 p67

O2-

ADPR

NO

PN
DNA damage

PARG

Ca2+

PAR
PARP

Endothelia l dysfunctio n

Treatment of vascular risk factors slows down the progression of dementia in patients with pure AD

Deschaintre et al., Neurology 73: 674, 2009

The neurovascular unit in health and disease


Hypertension Aging Alzheimers disease

USC Health

Perivascular cell

Neurovascular dysfunction

Oxidative stress
Cerebral Arteriole

Astrocyte

Neuron

Inflammation

Cognitive impairment

Acknowledgements

Drs. L. Park, J. Arather

Drs. C. Capone and G. Faraco

Drs. Steve Younkin and George Carlson NIH (NINDS, NHLBI), American Heart Association Alzheimers Association, Alzheimers Drug Discovery Foundation