Neurovascular Regulation in Health and Disease

Costantino Iadecola, M.D.Brain and Mind Research Institute

Weill Cornell Medical College

New York, NY, USA

Brain vascularization and the neurovascular unit

Nat Neurosci Rev 5: 347, 2004

ASTROCYTE

END-FEET

ENDOTHELIAL

CELL

FUNCTIONAL HYPEREMIA

TIGHT

JUNCTION

AUTOREGULATION

MEAN ARTERIAL PRESSURE (MMHG)50 150

CH

AN

GE

INC

BF AUTOREGULATED

RANGE

100

0

-50

+50

fMRI BOLD

FUNCTIONAL

IMAGING

MYOCYTE/PERI

CYTE

SYNAPTIC

ACTIVITY

Mechanisms of Cerebrovascular Regulation

Multiple agents and cells mediate the increase in CBF

evoked by activation

NO

GABA

5HT

NE

ACh

DA

SP

NT

VIP

SOM

NPY

H+K+ NO, PGs

Glu

Ado

Central pathwaysInterneurons

Ca++NOS

COX-2 ATP

Ado

Glu

K+ siphoning

P450

PGs

COX

Ca++ waves

Ca++

EETs

Ca++

mGluR

ATP Ado

GJ

Arteriole

Brain Lang 102: 141-152, 2007

Astrocytes

Synaptic activity

Perivascular

cells

CerebralArteriole Astrocyte

•••

Neuron

•

••

•

•

Myocyte/Pericyte Endothelium

Axon

The Neurovascular Unit: Beyond Blood Flow Regulation

Acta Neuropathol 120:287, 2010

Flow regulationBBB

exchangeImmune

surveillanceTrophic support(vascular niche)

Hypertension

Aging

Alzheimer

Do Cerebrovascular Factors Contribute to Alzheimer’s Disease?

1. Cerebral blood flow is reduced in pre-symptomatic individuals at genetic riskfor AD, cerebral blood vessels are notnormal;

2. AD and cerebrovascular diseases sharesimilar risk factors (hypertension,dyslipidemia, obesity, etc.);

3. Small ischemic lesions aggravate thedementia in patients with mild ADpathology (The Nun Study).

Nat Rev Neurosci. 5:347, 2004

Neuronaldysfunction

A peptides

Do vascular factors contribute to the

mechanisms of Alzheimer’s disease?

Cell. Mol. Neurobiol, 23:681, 2003

Vascular dysfunction

?

Ringer or

AcetylcholineCBF

Neocortex

CPThal

Methods to investigate neurovascular regulation in mice

100

130

CB

F %

incr.

60

100

MA

Pm

mH

g

Stim.

Field potentials

Functional hyperemia, endothelium-dependent vasodilatation (acetylcholine, A23187),

smooth muscle function (adenosine)

Neural and vascular CBF responses are attenuated inTg2576 mice at an early age

Whisker Stimulation Acetylcholine0

10

20

30

40

CB

F (%

incr

ease

)

Wild Type APP mice

*

* p<0.05; n=5/group

*

APP mice (age 3 months)

0 50 100 150 200-100

-50

0

50

100

150

Mean arterial pressure (mmHg)

CB

F (%

ch

ange

)

Wild type

APP mice

AJP 2002; 283:H315Nat Neurosci 2:157,1999; PNAS 97:9735, 2000

Smooth muscle function not affected

Vascular dysregulation increases the

susceptibility to ischemic injury in Tg2576 mice

Time after MCA occlusion (min)

Infarct volume

J. Neurosci 76:1755, 1997

*Resting flow: Non-Tg: 148±1; Tg: 105±9 ml/100g/min

Intraischemic CBF

AD patients have more strokes than age-matched controls

NOX p22

p47

NADPH oxidase

Rac1p67

Serine

phosphorylation

R

PKC

Ligand

O2-•

Cellular dysfunction

NADPH oxidase is a major source of free radicals in cerebral blood vessels in AD models

Tg2576 mice

JCBFM 24:334, 2004

3-NT

Developing APP mice deficient in NOX2

Tg2576 Tg2576/NOX2-/-

NOX2-/-Tg2576 X

Nox2 deficiency rescues neurovascular dysfunction and behavioral deficits in Tg2576 mice

PNAS 105: 1347, 2008

Old (12-15 months)

ROS

(DHE)Tg2576/Nox2-/-Tg2576

Whisker stimulation

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

10

20

30A

*#

*

CB

F (

% in

cre

ase)

Acetylcholine

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

10

20

30B

*

#

*

CB

F (

% in

cre

ase)

Bradykinin

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

10

20

30C

*

#

*

CB

F (

% in

cre

ase)

Adenosine

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

10

20

30

40D

CB

F (

% in

cre

ase)

Young (3-4 months) Aged (12-15 months)

Whisker stimulation

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

10

20

30A

*#

*

CB

F (

% in

cre

ase)

Acetylcholine

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

10

20

30B

*

#

*

CB

F (

% in

cre

ase)

Bradykinin

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

10

20

30C

*

#

*

CB

F (

% in

cre

ase)

Adenosine

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

10

20

30

40D

CB

F (

% in

cre

ase)

Young (3-4 months) Aged (12-15 months)

Whisker stimulation

Young (3-4 months)

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

25

50

75

100

*

A

No

ve

l a

rm e

ntr

y (

%)

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

50

100

150B

* *

Tim

e i

n n

ov

el

arm

(s

ec

)

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

25

50

75

100

*

A

No

ve

l a

rm e

ntr

y (

%)

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

50

100

150B

* *

Tim

e i

n n

ov

el

arm

(s

ec

)Cognitive function

Lipid raft

CD36

NOX p22

p47

NADPH oxidase

Rac1 p67

Serine phosphorylation

O2-•

A

Vav-GEF

Oxidativestress

Nucleusinflammation

NF-κB

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

Deletion of CD36 prevents the neurovascular

dysfunction and oxidative stress in Tg2576 mice

Radicals

PNAS 108: 5063, 2011

Tg2576 Tg2576/CD36-/-

Tg2576 X CD36-/-

CD36 deletion reduces cerebral amyloid angiopathy, but not amyloid plaques

PNAS 110: 3089, 2013

No difference in plaque load or microglial density

Deschaintre et al., Neurology 73: 674, 2009

Treatment of vascular risk factors slows down the

progression of dementia in patients with AD

Cognitive impairment

•••

Perivascular

cell

CerebralArteriole Astrocyte

Neuron • ••

••

Neurovascular

dysfunction

Hypertension Alzheimer’s diseaseAging

USC

Health

•Oxidative stress

•Inflammation

The neurovascular unit in health and disease