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CEREBRAL BLOOD FLOW
AND METABOLISM
Part 6 – 2016
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Cerebral Circulation
Blood flow to CNS
delivers O2, glucose, nutrients
removes CO2, lactic acid, metabolites
Cerebral vasculature
unique anatomy & physiology
safety mechanisms
Brain highly vulnerable to disrupted blood flow
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Vasoactive metabolites
neurotransmitters
ENDOTHELIUM
Vascular smooth
muscle
PARENCHYMA
LUMEN
Vascular Regulation
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Vascular Regulation
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Nurovascular Unit at Work
Neurology 2007;68:1730-1732
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Topic Contents
• Structure and functions of vascular
endothelial cell.
• The endothelial dysfunction.
• The oxidant- stress induced
endothelial dysfunction.
• How to assess endothelial functions.
• Summary
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Components:
Endothelial cells
Basement membrane
Glia
Transport:
Diffusion
Receptor mediated
transport
Ion channels
Blood-Brain Barrier (BBB)
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The Normal Vascular Endothelium
Historically viewed as a passive
vascular lining
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Vascular Endothelium
It has many important roles to maintain vascular
homeostasis:
Vascular tone regulation
Vascular smooth muscle cell proliferation
Inflammatory responses
Haemostasis
It produces and releases vasoactive,
thromboregulatory and growth factor substances
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Structure of Vessels
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Endothelial Cell Function
• Maintaining the
vascular tone:
Vasodilation and
Vasoconstriction
Tousoulis et al., Heart 2005; 91: 353-358.
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Endothelial Cell Functions
Functional targets Physiological action/Mediators
GrowthStimulation Inhibition
PDGF, FGF, IGF-1, ET, AII NO, PGI2, TGF
Inflammation
Proinflammatory Antiinflammatory
Adhesion molecules
Selectin-E, VCAM-1, ICAM-1, PECAM-1
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Endothelial cell functions
Calles-Escandon and Cipolla, Endocrine Rev 2001; 22: 36-52.
Functional targets Physiological action/Mediators
HemostasisProthrombotic Antithrombotic
PAI-1 PGI2, TPA
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Factors Affecting Vascular Tone and
Structure
Dilation
Growth inhibition
Atithrombotic
Anti-inflammatory
Antioxidant
Constiction
Growth promotion
Prothrombotic
Proinflammatory
Pro-oxidant
Endothelium maintains vascular health
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- pathological conditions
- altered anticoagulant &
anti-inflammatory properties
- impaired modulation of
vascular growth &
dysregulation of vascular
remodeling
An impairment of endothelium-dependent vasorelaxation
caused by a loss of NO bioactivity in the vessel wall
Endothelial Dysfunction
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Causes and Consequences of
Endothelial Dysfunction
Endothelial
dysfunction
Vasospasm
(coronary, cerebral)
Atherosclerosis
Inflammatory disease
Peripheral artery
disease
Reperfusion injury
Hypertension
ReocclusionHeart failure
Diabetes
Hyperhomocysteinemia
Hyperlipidemia
Immune reaction
Rubanyi GM. J Cardiovasc Pharmacol. 1993;22(suppl 4):S1-S4.
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Unifying Model: Endothelial Dysfunction
to Cardiovascular Disorder
Xanthine oxidase, NADP/NADPH oxidase
uncoulpled eNOS
NO bioavailability
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The Role of Endothelium in
Leukocyte Function
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How Can We Assess the
Endothelial Function?
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Furchgott, R., Zawadzki, J., “The Obligatory
Role of Endothelial Cells in the Relaxation of
Arterial Smooth Muscle by Acetylcholine,”
Nature, vol. 288, Nov. 27, 1980, pp. 373-376;
The Nobel Prize in Physiology or Medicine 1998
Robert F. Furchgott, Louis J. Ignarro, Ferid Murad
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Furchgott's Sandwich
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The L-arginine: Nitroc Oxide Pathway
Vallance P , Chan N Heart 2001;85:342-350
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What is Nitric Oxide (NO)?
NO is one of the most powerful,
endogeneous vasodilators
Vasodilators improve circulation
throughout the body
In 1998 The Nobel Prize in
Physiology or Medicine was
awarded to 3 Americans for
their discoveries concerning the
Nitric Oxide molecule in the
cardiovascular system Robert F. Furchgott
Louis J. Ignarro
Ferid Murad
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Why Does the Body Need NO?
The Answer: Better Circulation
Dilates existing vessels;
arterioles, venules and
lymphatics
Angiogenesis - the growth of
new blood and lymph vessels
Decreases edema and swelling
Increases nutritional flow to
cells
Increases antibiotic delivery
and action
Restores blood flow to nerves
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(A) In most, if not all, vessels nitric oxide is synthesised within the endothelium.
Vallance P , Chan N Heart 2001;85:342-350
©2001 by BMJ Publishing Group Ltd and British Cardiovascular Society
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Regulation of NO Synthesis
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Methods for exploring endothelial function.(Guerci et al., Diabetes Metab 2001; 27: 425-434.)
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Flow-mediated Vasodilation
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Endothelial Function
Dilation
Growth inhibition
Atithrombotic
Anti-inflammatory
Antioxidant
Constiction
Growth promotion
Prothrombotic
Proinflammatory
Pro-oxidant
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Endothelial Dysfunctionthe sine qua non of the atherogenic process
Age
Family history
Smoking
Hypertension
Low HDL-C
High LDL-C
Diabetes Mellitus
Dilation
Growth inhibition
Atithrombotic
Anti-inflammatory
Antioxidant
Constiction
Growth promotion
Prothrombotic
Proinflammatory
Pro-oxidant
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Hypercapnia-induced Vasodilation is Endothelium-
dependent and Sensitive to IschemiaP
erc
en
t C
ha
ng
e fro
m B
ase
line
0
5
10
15
20
25
30
35
40
10% CO2
5% CO2
control 1 hr 2 hr 4 hrPost - Ischemia
+
+
+*
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+
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Bari et al, Brain Res, (1998)