Contents
Part 1: Introduction – Background Information...............................................................................................1
Part 2: Cerebral Vasculature and Blood Flow................................................................................................1
Part 3: Acute Ischemic Stroke........................................................................................................................ 6
Part 4: Hemorrhagic Stroke......................................................................................................................... 13
Part 5: Treatment of Strokes........................................................................................................................ 14
Part 1: Introduction – Background Information
Stroke: brain injury caused by abnormality of blood supply to the brain
Types:
1. Ischemia: lack of blood
a. Most (87%) of strokes are caused by a clot blocking an artery which blocks blood supply to
the brain
2. Hemorrhage: bleeding in the skull
Effects of Stroke
The brain has few energy stores and can therefore only survive a few minutes without oxygen
high energy demand
Therefore, it is essential that the brain receives an adequate blood supply at all times
Stroke is associated with mental and physical impairment
A stroke occurs every 5 minutes in the UK, every 2 seconds in the world
Fourth single cause of death; 2% of whole population are stroke survivors
Costs the NHS and social care system 1.7 billion per year
What causes loss of blood flow that leads to stroke as you get older, you have more
atherosclerosis in the arteries which prevent blood flow
Part 2: Cerebral Vasculature and Blood Flow
Brain Energy Requirements
https://www.nature.com/articles/456715a.pdf
Structure of Cerebral Microvasculature
Cerebral microvessels: capillaries, arterioles and venules that provide blood flow to cortex and subcortical
structure
1. Cortical arterioles arranged in hierarchical vertical hexagonal assays
2. Orthogonal flow from pial surface to deeper layers
3. Penetrating arteriorles dive into cerebral cortex surrounded by the Virchow-Robin space
4. As arterioles penetrate deeper and arborise, the Virchow-Robin space disappears allowing the glia
limitants (formed by astrocyte end feet) to abut the media and fuse with the basal lamina
5. Further arborisation = transition to ternary microvessel structure called capillaries
o Capillaries have no adventitia
o Composed of endothelium circumferentially bound to basal lamina and astrocute end-feet
6. Pericytes found embedded in basal lamina in association with endothelium
7. Endothelial cells + astrocyte end feet = primary permeability barrier of cerebral microvessels
Normal: 50-60 mL/100g per minute
- Flow in gray matter = 4x flow in white matter
Abnormal
<16 mL/100g per minute = electrical failure isoelectric EEG
<10 mL/100g per minute = membrane failure cell death
<50 mL/100g per minute = reduced protein synthesis
<20 mL/100g per minute = disturbed energy metabolism and neurotransmitter release
10mL/100g per minute = terminal depolarisation with cellular potassium efflux
Argument: CNS blood flow is controlled by capillary pericytes
, Recent in vivo mouse studies have consistently shown that pericytes contract or dilate in response
to vasoactive mediators and physiological stimuli in line with earlier in vitro findings.
Importantly, these studies also illustrated that cortical and retinal capillaries dilated in close
synchrony with arterioles during sensory stimulation, supporting the view that blood flow in the
central nervous system is regulated at the capillary level as well.
Reinforcing the importance of pericytes in blood flow regulation, transgenic mice engineered to have
a reduced number of pericytes exhibited a deficient neurovascular coupling
What are Pericytes?
Present at 30um intervals along brain capillaries – major cell population
Seriously understudies
In the heart, pericytes are the 2nd most numerous cell type
Probably contribute to all diseases involving ischaemia as well as AD and cancer – largely ignored
Roles
Involved in vasculogenesis
Maintain BBB
Help form glial scar in spinal cord injury
Regulate leukocyte entry and movement in CNS
Control capillary diameter
Regulation of Brain Energy Supply via Arteriole Smooth Muscle vs Pericytes
Was originally though that blood flow increase evoked by neuronal activity reflects relaxation of smooth
muscle cells around arterioles but recently suggested that much of the flow increase is generated by
dilation of capillaries rather than arterioles by the relaxation of contractile pericytes
Pericytes designed ot produce a spatially localised constriction
65% of noradrenergic innervation of CNS vasculature is of capillaries, not arterioles
Pericytes constrict when stimulated (Peppiatt et al., 2006) can completely cut off blood flow
Pericyte constriction is calcium dependent (Peppiatt et al., 2006)
Signals spread between pericytes electrical signal goes along endothelial cells
Evidence: Hall et al., 2014 Supporting role of pericytes in regulating capillary blood flow
Aim Is blood flow controlled by arteriole smooth muscle or also by capillary pericytes?
controversial
Method Assessed signalling systems dilating molecular layer capillaries in cerebellar slices
Used 95% or 20% O2 in superfusate to produce a supra-normal or physiological
oxygen conc in the slice
Capillary pericytes identified by labelling for NG2 proteoglucan or the PDGFRB
receptor or employing mice expressing DsRed under control of NG2 promoter
Results 1. Applying NA to mimic release produced a sustained contraction mediated by
pericytes which was not affected by [O2]
2. Superimposing glutamate to mimic neuronal glutamate release dilated capillaries at
pericyte locations
a. Dilation was twice as large with 20% compared with 95% O2 due to less
production of vasoconstricting 20-HETE in low [O2]
3. Most pericytes constricted to NA and dilated to glutamate
4. More frequent occurrent of capillary dilation at pericyte locations and faster onset
of capillary dilation than arteriole dilation in vivo pericytes actively relax to dilate
capillaries
5. Mean arteriole dilation of 5.9% + capillary dilation of 6.7% increased steady state
blood flow by 19%
a. Omitting capillary dilation only increased flow by 3% shown to generate
84% of steady state increase in blood flow evoked by neuronal activity
6. Pericytes constrict and die in ischemia
a. Pericytes constrict the capillaries during ischemia, stay in this formation,
and then die
b. They do not relax after death because there is no ATP and they die in rigor
Conclusio pericytes are major regulators of cerebral blood flow and initiators of functional imaging
Part 1: Introduction – Background Information...............................................................................................1
Part 2: Cerebral Vasculature and Blood Flow................................................................................................1
Part 3: Acute Ischemic Stroke........................................................................................................................ 6
Part 4: Hemorrhagic Stroke......................................................................................................................... 13
Part 5: Treatment of Strokes........................................................................................................................ 14
Part 1: Introduction – Background Information
Stroke: brain injury caused by abnormality of blood supply to the brain
Types:
1. Ischemia: lack of blood
a. Most (87%) of strokes are caused by a clot blocking an artery which blocks blood supply to
the brain
2. Hemorrhage: bleeding in the skull
Effects of Stroke
The brain has few energy stores and can therefore only survive a few minutes without oxygen
high energy demand
Therefore, it is essential that the brain receives an adequate blood supply at all times
Stroke is associated with mental and physical impairment
A stroke occurs every 5 minutes in the UK, every 2 seconds in the world
Fourth single cause of death; 2% of whole population are stroke survivors
Costs the NHS and social care system 1.7 billion per year
What causes loss of blood flow that leads to stroke as you get older, you have more
atherosclerosis in the arteries which prevent blood flow
Part 2: Cerebral Vasculature and Blood Flow
Brain Energy Requirements
https://www.nature.com/articles/456715a.pdf
Structure of Cerebral Microvasculature
Cerebral microvessels: capillaries, arterioles and venules that provide blood flow to cortex and subcortical
structure
1. Cortical arterioles arranged in hierarchical vertical hexagonal assays
2. Orthogonal flow from pial surface to deeper layers
3. Penetrating arteriorles dive into cerebral cortex surrounded by the Virchow-Robin space
4. As arterioles penetrate deeper and arborise, the Virchow-Robin space disappears allowing the glia
limitants (formed by astrocyte end feet) to abut the media and fuse with the basal lamina
5. Further arborisation = transition to ternary microvessel structure called capillaries
o Capillaries have no adventitia
o Composed of endothelium circumferentially bound to basal lamina and astrocute end-feet
6. Pericytes found embedded in basal lamina in association with endothelium
7. Endothelial cells + astrocyte end feet = primary permeability barrier of cerebral microvessels
Normal: 50-60 mL/100g per minute
- Flow in gray matter = 4x flow in white matter
Abnormal
<16 mL/100g per minute = electrical failure isoelectric EEG
<10 mL/100g per minute = membrane failure cell death
<50 mL/100g per minute = reduced protein synthesis
<20 mL/100g per minute = disturbed energy metabolism and neurotransmitter release
10mL/100g per minute = terminal depolarisation with cellular potassium efflux
Argument: CNS blood flow is controlled by capillary pericytes
, Recent in vivo mouse studies have consistently shown that pericytes contract or dilate in response
to vasoactive mediators and physiological stimuli in line with earlier in vitro findings.
Importantly, these studies also illustrated that cortical and retinal capillaries dilated in close
synchrony with arterioles during sensory stimulation, supporting the view that blood flow in the
central nervous system is regulated at the capillary level as well.
Reinforcing the importance of pericytes in blood flow regulation, transgenic mice engineered to have
a reduced number of pericytes exhibited a deficient neurovascular coupling
What are Pericytes?
Present at 30um intervals along brain capillaries – major cell population
Seriously understudies
In the heart, pericytes are the 2nd most numerous cell type
Probably contribute to all diseases involving ischaemia as well as AD and cancer – largely ignored
Roles
Involved in vasculogenesis
Maintain BBB
Help form glial scar in spinal cord injury
Regulate leukocyte entry and movement in CNS
Control capillary diameter
Regulation of Brain Energy Supply via Arteriole Smooth Muscle vs Pericytes
Was originally though that blood flow increase evoked by neuronal activity reflects relaxation of smooth
muscle cells around arterioles but recently suggested that much of the flow increase is generated by
dilation of capillaries rather than arterioles by the relaxation of contractile pericytes
Pericytes designed ot produce a spatially localised constriction
65% of noradrenergic innervation of CNS vasculature is of capillaries, not arterioles
Pericytes constrict when stimulated (Peppiatt et al., 2006) can completely cut off blood flow
Pericyte constriction is calcium dependent (Peppiatt et al., 2006)
Signals spread between pericytes electrical signal goes along endothelial cells
Evidence: Hall et al., 2014 Supporting role of pericytes in regulating capillary blood flow
Aim Is blood flow controlled by arteriole smooth muscle or also by capillary pericytes?
controversial
Method Assessed signalling systems dilating molecular layer capillaries in cerebellar slices
Used 95% or 20% O2 in superfusate to produce a supra-normal or physiological
oxygen conc in the slice
Capillary pericytes identified by labelling for NG2 proteoglucan or the PDGFRB
receptor or employing mice expressing DsRed under control of NG2 promoter
Results 1. Applying NA to mimic release produced a sustained contraction mediated by
pericytes which was not affected by [O2]
2. Superimposing glutamate to mimic neuronal glutamate release dilated capillaries at
pericyte locations
a. Dilation was twice as large with 20% compared with 95% O2 due to less
production of vasoconstricting 20-HETE in low [O2]
3. Most pericytes constricted to NA and dilated to glutamate
4. More frequent occurrent of capillary dilation at pericyte locations and faster onset
of capillary dilation than arteriole dilation in vivo pericytes actively relax to dilate
capillaries
5. Mean arteriole dilation of 5.9% + capillary dilation of 6.7% increased steady state
blood flow by 19%
a. Omitting capillary dilation only increased flow by 3% shown to generate
84% of steady state increase in blood flow evoked by neuronal activity
6. Pericytes constrict and die in ischemia
a. Pericytes constrict the capillaries during ischemia, stay in this formation,
and then die
b. They do not relax after death because there is no ATP and they die in rigor
Conclusio pericytes are major regulators of cerebral blood flow and initiators of functional imaging
