Iadecola 2017 NVU

Question 1

Describe the vascular organization that feeds into the brain including the NVU

Answer 1

Internal carotid artery enters the head and branches off to Circle of Willis and middle cerebral artery -> Pial arteries (innervated by peripheral neurons -> penetrating arterioles (encased by endfeet and interneurons in close apposition) -> capillaries (encased by pericytes and astrocyte endfeet.

Question 2

Is there vascular heterogeneity across regions?

Answer 2

Yes, density correlates with activity though topology is conserved across cortex
More flow in inferior colliculus and lower in white matter

Question 3

What is functional hyperemia? What does this underlie?

Answer 3

Increased CBF in response to activated brain regions
This underlies fMRI due to spatiotemporal correspondence of neural and hemodynamic activity

Question 4

Is hemodynamic response always faithful to activate brain regions?

Answer 4

Not necessarily
Auditory and visual cortex don’t have exact match between activated area and blood flow

Question 5

What can promote angiogenesis in the developing brain?

Answer 5

hypoxia

Question 6

Why does CBF increase with brain activity?

Answer 6

Delivery of oxygen and glucose
Also clearance of waste products like CO2, Abeta
Indeed by products can increase flow

Question 7

Which of feedback or feedforward model is applicable to functional hyperemia?

Answer 7

Recent model is feedforward but evidence for both
Feedback = metabolic byproducts driving dilation
Feedforward = release of vasoactive products due to synaptic activity to drive dilation
Synaptic activity can release vasoactive products to increase flow via feedforward, and the reduced O2 due to consumption can produce metabolic byproducts to have feedback effects

Question 8

How may vasculo-neuronal coupling occur?

Answer 8

Increased blood flow can cause mechanosensation via astrocyte TRPV4 to influence pyramidal neuron activity

Question 9

Describe generally how neurons can contribute to NVC.

Answer 9

Synaptic activities can activate AMPAR and NMDAR to increase Ca2+ -> activate Ca2+-dep proteins like nNOS and COX2 to produce NO (via GC) and PGE2 (via EP2 and EP4)
Glutamates activate astrocyte mGluRs for Ca2+ signaling
They can also release K+ during repolarization -> vasodilator

Question 10

How do different neuronal subtypes differ in contribution to NVC?

Answer 10

• Pyramidal cells (major excitatory neuron in cortex) partake in hyperemia through the general mechanisms of NO, PGE2, K+
• GABA interneurons cause biphasic dilation and constriction response by NO and neuropeptide Y
• Subcortical projection neurons often terminate on astrocyte endfeet (eg. BF cholinergic) -> involved not in CBF by neural activity but more for maintaining resting CBF and modulating CBF increase
• Also noradrenergic projections from locus coeruleus for vasoconstriction to focus oxygen to activated areas

Question 11

What do astrocytes do and through what pathways can it affect NVC?

Answer 11

• Astrocytes bridge neurons and vasculature to communicate and release vasoactive molecules
• mGluR5 (by glutamate) or P2X (by ATP) increase intracellular Ca2+ to activate PLA2/D2 to activate COX-1 or p450 -> metabolize arachidonic acid to PGE2 or to EET
• Can also release K+ through BKCa to activate vascular Kir channels for dilation

Question 12

What divergent activities are seen in astrocytes?

Answer 12

Fast and slow Ca2+ increases
Fast = likely to happen when animal is more active during NVC
Slow = happens regardless of activity but is still augmented by activity during NVC

Question 13

What do endothelial cells do in NVC? What is the mechanism that underlies this?

Answer 13

Retrograde propagation of vascular response from capillary to upstream arterioles
Endothelial lesions disrupts propagation beyond the lesion site

Kir2.1 allows hyperpolarization at low <10mM K+ (but would depolarize at very high 30mM-60mM concentrations
-> propagate through gap junction and to SMC by myoendothelial junctions

Alternatively slower Ca2+ increases can allow hyperpolarization through IK/SK channels too

Question 14

What do SMCs and pericytes do in NVC? Through what pathways?

Answer 14

SMC can dilate through:
- NO on GCs
- PGE2 on EP4
- K+ on Kir2.1
Constrict through:
- 20-HETE -> activate TRPC6 -> Ca2+ influx
- ET-1 on ETA

Pericytes can dilate through:
- PGE2 on EP4
Constrict through:
- ET-1 on ETA
- Produce 20-HETE from AA via p450

Question 15

How do ECs relate to adult neurogenesis?

Answer 15

ECs in the HPC produce BDNF required for neurogenesis

Question 16

How do astrocytes and pericytes contribute to BBB? What about glymphatic system?

Answer 16

Astrocytes secrete sonic hedgehog to tighten the BBB and promote anti-inflammatory environment to decrease leukocyte infiltration (implication in MS)
Pericytes can form junctions with endothelial cells to promote barrier integrity

Aqp-4 on astrocytes promote CSF flow in glymphatics

Question 17

What sorts of NVU and BBB alterations are seen in early AD?

Answer 17

Reduced resting CBF and BBB permeability (increased PDGFRbeta due to pericyte degeneration)

Question 18

How may perivascular macrophages relate to AD vascular pathology?

Answer 18

Abeta acting on CD36 induces vascular oxidative stress
They can also promote CAA by accumulating Abeta