Regulation and Pathology of the Cerebral Circulation-Extra Reading Flashcards
Iadecola, Nature, 2007
-Understanding of astrocytes has advanced our understanding of cerebral blood flow-they participate in the increases in flow evoked by synaptic activity
-Astrocytes are distributed in NON-OVERLAPPING domains
^this means they are uniquely positioned to shape the spatial distribution of vascular response, but is also bad because if they are damaged, then neurones are cut off with no back up
-Astrocytic calcium is an important determinant of microvascular function
ANATOMY
- brain arteries e.g anterior, posterior, middle and those from the circle of willis travel along the brain surface to form PIAL ARTERIES
- pial arteries then DIVE into the brain parenchyma to form penetrating arteries
- Penetrating arteries are separated from the brain parenchyma by an extension of the subarachnoid space called VIRCHOW-ROBIN SPACE
- Penetrating vessels reach deeper until they eventually reach direct contact with astrocytic end feet
- Deep within the brain the vessels become capillaries-merely endothelial cells on a layer of basal lamina surrounded by pericytes and in contact with astrocytic end-feet
- Pericytes are contractile
- In addition to pH, adenosine and K+, there is the widely accepted hypothesis that activation of GLUTATMATE receptors during synaptic transmission between neurons causes post synaptic increases in Calcium-CALCIUM SPIKES that induce the release of vasoactive agents from the endothelium e.g NO and NPY
- astrocytes cover 99% of cerebral vascular surface
- Studies of astrocytes proved that neuronal stimulation increased calcium concentration in endfeet leading to a slow-developing dilatation of local cerebral arterioles
- The study proved that the cause of this was glutamate stimulation when glutamate blockers were used and the response vanished
-Astrocytes are able to communicate with one another via gap junctions-so they can integrate the overall synaptic activity of a region
WHAT HAPPENS TO CEREBAL BLOOD FLOW IN SEIZURES?
-Large and sustained increases in blood flow cannot be achieved by flow distribution alone
-This needs large upstream artery dilation to allow the maintained increase in blood flow and this is thought to occur because of retrograde propagation of vasodilators
^Astrocytes are key determinants in cerebral blood flow so may be a therapeutic target in diseases of cerebral hyperperfusion such as epilepsy
WHEN SYSTEMIC PRESSURE INCREASES, CEREBRAL VESSELS CONSTRICT TO PROTECT THE BRAIN
WHEN SYSTEMIC PRESSURE DECREASES, CEREBRAL VESSELS RELAX TO BOOST FLOW TO THE BRAIN
THEORY FOR AUTOREGULATION
-it is thought that increases in pressure trigger stretch-activated calcium channels which increases cellular calcium levels
calcium results in a cascade that produces arachidonic acid which is metabolised to 20-HETE
20-HETE inhibits K+ channels causing smooth muscle cell depolarisation and thus SMC CONSTRICTION
Melikian, 2009
- NO plays a KEY paracrine role in regulation of vessel tone both under rest and increased blood flow
- It was originally thought that eNOS derived NO was largely responsible for regulating cerebral blood flow, however this has been CHALLENGED by studies using an inhibitor of NEURONAL NO Synthase (nNOS): SMTC
- Studies show that SMTC reduces basal blood flow in human arms and coronary vessels WITHOUT affecting eNOS mediated vasodilation
i. e SMTC inhibited nNOS but eNOS not affected-INDICATING THAT THE NO HAS DIFFERENT ROLES - Suggests that both eNOS and nNOS have distinct roles in the physiologic local regulation of human microvascular tone
- Was originally thought that eNOS was the main isoform in the control of vascular endothelium but this study shows that nNOS also plays a role in controlling vasculature
- studies also showed that inhibiting nNOS demonstrated a reduction of mental-stress induced vasodilation-so nNOS must play a role in the functional hyperaemic effect
Goldberg, Stroke, 2003
- The traditional view was that grey matter was more vulnerable to ischaemia but this was probably due to the fact that the majority of animal studies were conducted on rodents of whom have only 14% white matter
- White matter has a metabolic rate fractionally lower than grey, but it is the oligodrendrocytes that make white matter very vulnerable to ischaemia
- Recent studies have demonstrated that white matter can be damaged by even the briefest of ischaemia
- Rodent studies have shown that hypoxia leads to axonal dysfunction by activation of voltage-dependent Na/Ca channels which causes intra-axonal calcium accumulation and thus faulty conduction
- New data also shows that the damage is not just refined to axonal cells, but to microglia, oligodendrocytes and astrocytes too
- White matter is injured by HYPOGLYCAEMIA as well as hypoxia because the majority of respiration in the brain uses glucose as a substrate
- Studies show that glycogen stores play a protective role but only astrocytes are able to store glycogen
- Oligodendrocytes are HIGHLY vulnerable to hypoxia/energy deprivation or oxidative stress
- In hypoxia, synapses misfire resulting in accumulation of glutamate and excitiotoxity
- Oligodendrocytes have AMPA receptors for glutamate and are one type of cell that can be killed from over-stimulation of glutamate receptors
- Recent studies have shown that AMPA-excitotoxicity is involved in the pathways that cause periventricular leukomalacia, traumatic spinal cord injury and allergic encephalomyelitis
- Oligodendrocyte injury impairs conduction through its effects on Myelin
- Studies have shown that AMPA-inhibitors reduce white matter injury in rodent models of spinal cord ischaemia and transient focal cerebral ischaemia so perhaps AMPA-ANTAGONISTS COULD BE USED THERAPEUTICALLY
- AMPA-Antagonists are now reportedly entering late phase clinical trials
IMAGING OF WHITE MATTER
- Hyperintense white matter on CT and MRI scans have been linked with Hypertension, cognitive impairment and are hypothesised to represent regions of microvascular ischaemic pathology
- Could potentially be used as a future prognostic measure
FUTURE PERSPECTIVES
- White matter could be a target for future therapies to reduce the clinical deficits seen after brain ischaemia
- Studies using INOSINE that promotes axon sprouting and MONOCLONAL ANTIBODIES to block myelin inhibitory factors are both showing promising results that will hopefully be useful in the near future
Quaegebeur, Neuron, 2010
-Progressive age-dependent loss of pericytes around brain microvessels impairs brain perfusion, disturbs vasoreactivity and induces BBB leakage which all allows neuronal damage and neurodegeneration
^This is confirmed by several other studies which clarifies the fact that pericytes are NOT MERELY BYSTANDERS in the safeguard of the BBB but play an integral role in its maintenance
-BBB discovered when dye was injected into the brain by EHRLICH 1885 and it was taken up by all tissues except the brain
- Pericytes establish physical interactions with endothelial cells via peg-socket contacts
- In vessel maturation, Pericytes are recruited via Endothelial secretion of PDGF-beta
- PDGF-beta knockout mice have very few pericytes and exhibit leaky blood-brain barriers
- Studies show that ageing mice show particular degeneration of the Hippocampus and Cortex
- Vascular changes including loss of pericytes was observed before any neurodegeneration was observed, which indicates that neuronal injury is a consequence of pericyte loss and lack of BBB integrity
- Pericyte deficient models showed bigger neuronal loss
- Hypoxia causes residual pericytes to constrict which further declines perfusion
- Pericytes have also been shown to possess neural stem cell capacity so in pericyte deficient models, repair after injury is halted
- BBB deficits have been documented in Alzheimer’s and other neural conditions which indicate that pericytes are a lot more involved in neurovascular disorders than previously thought
- Daneman et al showed that Pericytes are needed to release Angiopoietin-1 which is used to maintain blood-brain barrier integrity
