Foundation - BBB Flashcards
What’s so unique about the blood in the brain?
One of the highest metabolic demands in the body
- Needs a lot of oxygen.
- Needs a constant carbon source
(where get energy from. glucose - preferred source)
- Generates a lot of waste.
What’s in the blood?
- 55% of it is water!
- Lots of ions and molecules
blood in the brain requires a tight control of water and ion concentrations because
-Little space for liquid inside the head
-Ionic strength of extracellular and intracellular milieu (enviorment) critical for action potentials
Cerebral circulation behaves different than peripheral circulation because
- Has to provide large volumes of blood
- Has to provide a constant supply
- Has to be insensitive to fluctuations in blood pressure (brain capillaries very small, high bp -stroke)
- Work together with Choroid Plexus to generate CSF
- Essential part of the glymphatic system (remove waste)
The BBB functions
- Allow uptake of glucose
- Allow removal of waste
- Allow gas exchange
- Control cellular migration
- Formidable barrier for pathogens!
types of vessels
- Arteries (carry oxenginated blood)
- Veins (cary away “spent” blood)
- Capillaries (allow gas exchange)
vessels are made up by
endothelial cells
Line the inside of all vessels
types of endothelium
- Continuous - CNS vessels (except ventricles)
- Fenestrated
- Sinusoid (or discontinuous)
endothelium vs epithelium
endothelium - lines the vasculature and ensures tissue supply with nutrients and oxygen (BMECs - endothelial act like epithelial)
epithelium - forms the barrier between tissues and the outer environment thus protecting organs from invading harmful agents (Ependymal - B-CSF)
collaterals that ensure blood flow into the brain
1) The Circle of Willis
2) Pial network of vessels in the meninges
Blood supply to the brain is from
4 large arteries coming directly from aorta
* Left/right internal carotid
* Left/right vertebral artery
Brain supply of blood is ~80% from
carotids, rest from vertebral arteries
Spinal cord blood supply is
all from vertebral arteries
Carotids vs Vertebral blood supply - where go
Carotids - mostly cerebrum
Vertebral - mostly cerebellum and brain stem
the Circle of Willis
where carotid and Vertebral arteries
all join in the base of the brain in a ring
The Circle of Willis give rise to the
next 3 main arteries that supply blood to the rest of the brain (anterior, middle, and posterior cerebral arteries)
The Circle of Willis allows
1) redistribution of blood if one or more of the main arteries are occluded
2) Low resistance (pressure), allows blood flow to go either way in the ring
Anatomy of the Main arteries
NO BBB in circle of willis
- Extracellular matrix and nerve cells
- Smooth muscle layers (up to 20) - regulate pressure
- Endothelial layer (contains dozens of ECs)
Anatomy of the Pial arteries
~3 smooth muscle layers
Anatomy of the Intracerebral arteriole
- Pericytes and astrocytic endfeets
- 1 layer of smooth muscle
Anatomy of the Microcapillary
- Specialized ECs and no smooth muscle
(a.k.a. the BBB) - one endotheal cell - covers whole circumfrance of BBB - where two ends tough - tight junctions
- endotheal cell that acts like epitheal cell
3 barriers of the CNS
- BBB – at the level of the microcapillaries - impermiable
- Blood-CSF – at the choroid plexus - selectivly permeable
- Blood-meningeal – in the arachnoid space - less impermeable (enchepalitis)
Where is there fenestrated endothelium in the brain
- Surface intracranial vessels (in the dura)
- Choroid plexus vessels
allow exchange
Blood drainage in the brain occurs from
inside towards the surface: major sinuses
All sinuses join with the jugular
The BBB is ONLY Present in
the capillary beds of the brain
(microcapillaries)
The BBB is formed by
- Special endothelial cells known as BMECs
- Pericytes (a type of mural cell)
- Astrocytes (their endfeet)
- Basal (or basement) membrane - [a thin, dense layer of extracellular matrix that lines most human tissues forming the supporting structure and scaffolding]
- Microglia (constantly surveying the
microvessels for “insults”)
Functions of the BBB
- Control molecular traffic: CO2 and O2 permeable; lipid soluble permeable; small peptides (<400 Daltons) permeable
- Ion homeostasis: anything ionic impermeable
- High affinity for nutrients: active transport by protein transporters
- Controls cellular traversal: Immune surveillance with minimal inflammation
Unique features of BMECs
TJs - restricts paracellular passage
Very low rates of transcytosis (movement of molecules between opposite sites in a cell): restricts transcellular passage
Passage can be regulated by cellular transporters– localized at specialized domains: apical or basal
High number of mitochondrias (to power transporters)
Cellular transporters in BMECs
Efflux transporters
- Apical side
- Bind lipophilic (lipid-soluble) molecules inside the cells and transport them back to the blood
Influx transporters
- Both sides (apical and basal)
- Highly specific nutrient channels
Types of cellular junctions in BMECs
- Tight junctions (TJs) - seals space
- Adherens juntions (AJs) - link actin fillamints - provides shape + support
- Desmosomes - link intermediate filamints - strength and elasticiity
- Gap junctions - link cytosol of neighboring cells
TJs in BMECs
paracellular (between cells) barrier to ions, molecules, and cells
Can be homotypic or heterotypic interactions
Claudins, Occludins, and Junctional adhesion molecules (JAMs)
Interactions are so tight, that cellular traversal in the CNS occurs mainly by transcellular pores (imagine a donut)
AJs in BMECs
similar organization to TJs, but further away from apical side
- Cadherins, in BMECs, is (VE)-cadherin
- Linked to the actin cytoskeleton of the cell
- Ca+2 regulated, hence they are major regulators of permeability
- Main type of endothelial cellular junction in the brain outside the BBB
so tight - immune cells cannot cross under normal conditions - if immune needs to go through - goes through cell
LAMs in BBB
Leukocyte adhesion molecules (LAMs - need for immune to cross) - Low levels
LAMs are upregulated during certain diseases: TJ are disassembled, and JAMs exposed - cellular infiltration
- Commonalities between diseases
Key feature of BBB is provided by __but ___
BMECs
but cannot do it (form BBB) by itself
- properties are induced by inerations with other compoenents of the BBB (NVU - neuro vasculature unit)
Pericytes (PC)
are ____ (where)
general roles ____
CNS specific roles ___
Embedded in the basal membrane of vasculature - take on role of smooth muscles (1 of 2 levels of basal membrane)
- PC:EC ratio 1:3 in CNS; 1:100 in skeletal muscle
Several roles in general:
- Elasticity and rigidity (vessel diameter regulation)
- Angiogenesis, extracellular matrix production
Specific roles in CNS:
- Regulates immune cell infiltration
- Regulates permeability of the BBB
- They inhibit features normal in the peripheral vasculature
w/o - absence of trancitosis and inc LAMs
Astrocytes (ACs)
produce many factors that regulate BBB permeability
They increase the TEER = decrease
permeability
Can regulate blood flow through secreted
molecules that act on PCs
Provide second layer of support (secrete
extracellular matrix)
Basal (basement) membrane
Two layers: vascular and parenchymal layers
Composition differ from that in peripheral
vasculature
Support function, but also barrier function
Enzymatic degradation is needed to traverse the basal membrane
Microglia constantly surveying the basal membrane
BBB issues in disease
- Stroke
- Multiple sclerosis
- Parkinson’s disease
- Alzheimer’s disease
- Epilepsy
- Traumatic brain injuries
- Infectious diseases
Similar pathologies!
* ↑ permeability
* ↑ cellular infiltration
* Disruption ion/pH homeostasis
* Disruption neural function
connections with BBB destruction - between infectious and non-infectious
