Getting a grip on cerebral blood flow

1929_art_cap_pericyte_l.jpgThe brain, an energy-hungry organ which consumes one-fifth of the body’s energy, controls its own blood supply, which is no mean feat. All cells require a constant supply of oxygen and glucose (both of which are carried in the blood) and blood flow increases to discrete regions as groups of cells become active.

A beautiful paper by Peppiatt et al in today’s issue of Nature shows that cells called pericytes regulate blood flow through brain capillaries by controlling the diameter of the vessels.

Capillaries consist of two types of cells. Endothelial cells form the inner lining of the vessel, and perivascular cells (usually called pericytes) envelop the vessel on the outside.

Until quite recently, pericytes have been almost completely ignored and remained rather enigmatic. They have been called many different things – perivascular macrophages, perivascular microglia, granular perithelial cells, Rouget cells, Mato cells and mural cells – but this may also reflect sub-populations of cells which perform different functions in different places.

Pericytes are vascular smooth muscle cells which are derived from the bone marrow. They are found adjacent to blood vessels throughout the central nervous system, where they are continuously turned over, and in the peripheral nervous system. Mature pericytes are very complex cells which have finger-like projections that extend around the diameter of the capillary. These cells have been implicated in various pathological conditions; they are activated in animal models of inflammation, stroke, hypertension, and nerve cell injury and death. They have important immunoregulatory functions – they are involved in autoimmune disease and are targets for HIV – and are also involved in the development and maintenance of blood vessels. It is believed that pericytes are pluripotent, so that they retain the ability to differentiate into other cell types during the formation or regeneration of blood vessels.

Senior author David Attwell and his colleagues at UCL have conducted some very elegant electrophysiology experiments on pericytes in isolated retinae and slices of cerebellar tissue from rats. The experiments provide strong evidence that pericytes control blood flow in the microvasculature.

Using microelectrodes, they electrically stimulated the cell bodies of pericytes, causing their projections to close around the capillary, constricting it and impeding blood flow. They also used micropipettes to ‘puff’ solutions of ATP, noradrenaline and glutamate into their tissue preparations. ATP and noradrenaline caused constriction, and glutamate caused dilation, of the vessels. The vast majority of pericytes (90%) responded to electrical stimulation, but, in the cerebellum, only half responded to noradrenaline and, in the retina, one quarter to ATP, perhaps because of differential receptor gene expression.

The actions of ATP on the cells were then shown to be mediated by P2X and P2Y receptors. Occasionally, the signal evoking constriction of the capillaries propagated along the vessel at a speed of 2 micrometres per second, causing pericytes further along the vessel, but not the length of capillary in between, to constrict as well. This showed that it is the pericytes, and not the endo- thelial cells or the end-feet of astrocytes, which mediated constriction of the capillaries. The removal of calcium abolished the constriction evoked by electrical stimulation, confirming that the response of the pericytes to stimulation is caused by an increase in intracellular calcium concentration. Finally, it was shown that pericytes might be involved in the vasoconstriction that occurs after ischaemia (in which part of the brain is deprived of oxygen).

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At the beginning of this film clip of a slice of cerebellar tissue, noradrenaline causes the pericyte to constrict around the vessel, so that the erythrocytes (red blood cells) remain motionless in the top half of the screen. When glutamate is added, it acts upon the pericyte, which loosens its grip on the vessel, so that the cells can pass:

Thus it has been confirmed that pericytes control the diameter of capillaries, and therefore the changes of blood at the microscopic scale, in the retina and brain, in health and, perhaps, in disease. The findings challenge the idea that blood flow in the brain is controlled upstream of the capillaries by the larger arterioles. It is these small changes in blood flow that are detected by brain scanning techniques such as functional magnetic resonance imaging (fMRI), so an understanding of how they are controlled may enable both an improvement in these techniques and better interpretation of the signals produced by them. The findings also open up a new avenue of treatment for conditions such as ischaemia and stroke, in which blood vessels in the brain are damaged or cerebral blood flow is interrupted.

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