Vascular biology

Brain vessels squeezed to death

A study finds that contractile cells that surround the capillary vessels of the brain control the blood supply to healthy neurons, and that their death may aggravate brain injury by strangling vessels. See Article p.55

The human brain's two billion neurons are supplied with oxygen and nutrients by a network of cerebral blood vessels that equates to around 700 kilometres in length. Most of these blood vessels are tiny capillaries surrounded by contractile supporting cells called pericytes. When a major vessel that supplies blood to the brain becomes obstructed, capillary blood flow is interrupted, and this may deplete the brain's oxygen supply, causing rapid loss of neuronal function, cell death and stroke. In a paper published on page 55 today, Hall et al.1 show that pericytes have a crucial role in the normal regulation of cerebral blood flow, and that a lack of oxygen causes pericyte death and constriction of capillaries.

Around 140 years ago, the French physiologist Charles Rouget observed2 a population of cells lying in close proximity to capillary cells, which he hypothesized were involved in vessel contraction. Although initially termed Rouget's cells, they were subsequently named pericytes, to describe their location around capillaries. Of all the organs in the body, the brain has the highest density of pericytes. Brain pericytes are known to be needed for the development and maintenance of the blood–brain barrier3,4,5, which regulates exchanges between the brain and its vasculature, and to be involved in diseases associated with this interface6. However, the additional role for pericytes first suggested by Rouget — regulating cerebral blood flow — has not been demonstrated in the brain in vivo until now.

Neuronal activity stimulates blood supply by causing vessel dilation, a fact that is exploited by functional magnetic resonance imaging to allow mapping of the brain regions that are associated with different tasks. To determine the role of pericytes in vasodilation, Hall et al. first investigated the molecular signals regulating capillary dilation induced by neuronal activity in slices of rodent cerebellum. The authors found that pericytes relax their grip on capillaries in response to glutamate molecules, the key excitatory neurotransmitters in the brain. This causes the capillaries to dilate, directing more blood to active brain regions (Fig. 1a).

Figure 1: Cutting off the blood supply to the brain.
figure1

Hall et al.1 report that pericytes, which surround the endothelial cells that form capillaries, are involved in regulating cerebral blood flow. a, Blood flows into capillaries from feeding arteries. In response to neuronal activity, pericytes relax their grip on cerebral capillaries, causing blood-vessel dilation and increasing the oxygen supply to active neurons. b, Obstruction of a cerebral artery (which mimics the effects of ischaemic stroke) results in pericyte constriction and death, limiting blood flow and oxygen supply to neurons in the brain. c, The authors hypothesize that the no-reflow phenomenon occurs because of rigor mortis in dead pericytes, which causes continued strangulation of capillaries even after a blocked artery is reopened.

Next, the researchers investigated which branches of the cerebral vasculature are responsible for dynamic alterations in vessel diameter and blood flow. For example, is dilation of larger arterioles, induced by neuronal activity, sufficient to cause an increase in blood flow in smaller capillaries7, or is vasodilation initiated at capillaries? Previous research8 from the same group demonstrated that electrical stimulation of pericytes (which mimics neural activity) in isolated rodent retinas alters capillary diameter at the pericytes.

In the present study, Hall and colleagues used in vivo live imaging of vessels in the somatosensory cortex region of the mouse brain — which responds to sensory inputs — after electrical stimulation of the animal's whisker pad. In doing so, they demonstrated that relaxation of pericytes at the capillary level precedes relaxation of smooth-muscle cells (which surround larger arterioles and are involved in cerebral blood-vessel constriction) by about 1 second. Thus, pericytes surrounding capillaries initiate changes in local blood flow in response to neuronal activity, and thereby provide a sensitive control mechanism to match neuronal activity and blood supply throughout the brain. In support of the idea that capillaries are a primary site of cerebral blood-flow control, the terminals of one neuronal subtype (noradrenergic neurons) are typically found in proximity to capillaries, rather than near to arterioles9.

Hall et al. report that the resting diameter of capillaries is larger in areas where pericytes are present than in areas that lack these cells. Electrically stimulated dilations were more frequent and of larger magnitude in capillary areas with pericytes. Previously, embryonic mice that lack brain pericytes have been shown to develop microaneurysms10. Together, these results indicate that pericytes play a key part in the regulation of blood-vessel size. It would be informative to remove or reduce pericyte numbers in the central nervous system of adult mice, or to block the pericyte's ability to contract. Subsequent analysis of the changes in cerebral capillary blood flow induced by neuronal activity in these animals compared with controls would help to delineate a more precise role for pericytes in regulating blood flow in the brain.

Ischaemic stroke, caused by a lack of blood to the brain, has devastating effects. Treatments are limited because reperfusion strategies that aim to restore blood supply are effective within only around 4.5 hours of the onset of symptoms. Treatment efficacy is limited by time because reperfusion is impaired when the reopening of a large artery is delayed (known as the no-reflow phenomenon). Although controversial, persistent pericyte contraction after ischaemia has been implicated as a cause of the no-reflow phenomenon in capillaries11,12. Hall and colleagues demonstrate that, on exposure of rat brain slices to conditions simulating ischaemia, capillaries constrict and then pericytes die (Fig. 1b). Furthermore, the authors found that in rats, temporary obstruction of a cerebral artery in vivo induces substantial death of pericytes, but not of endothelial cells that make up the blood vessels.

Hall and co-workers suggest that the long-term reduction of cerebral blood flow after reperfusion of a blocked artery may be at least partly attributable to pericyte rigor mortis — literally 'the stiffness of death' (Fig. 1c). In rigor mortis, stiffness results from a lack of ATP molecules, which prevents myosin and actin — two proteins that interact to cause muscle contraction — from being separated from one another.

The concept of prolonged vasoconstriction due to strangulation by dead pericytes raises several questions that require further investigation. Why are pericytes, as opposed to other cell types such as endothelial cells, particularly susceptible to ischaemia-induced death? Can pericyte death be prevented, and will this inhibit the no-reflow phenomenon? Is pericyte rigor mortis a factor in this phenomenon after injury in other tissues, particularly in the heart following a heart attack? If this model of ischaemia-induced pericyte rigor mortis remains robust in the face of further analysis, it may pave the way for approaches to combat ischaemic injury that prevent pericyte-induced loss of a tissue's ability to reperfuse.

References

  1. 1

    Hall, C. N. et al. Nature 508, 55–60 (2014).

  2. 2

    Rouget, C. Arch. Physiol. Normal Pathol. 5, 603–663 (1873).

  3. 3

    Daneman, R., Zhou, L., Kebede, A. A. & Barres, B. A. Nature 468, 562–566 (2010).

  4. 4

    Armulik, A. et al. Nature 468, 557–561 (2010).

  5. 5

    Bell, R. D. et al. Neuron 68, 409–427 (2010).

  6. 6

    Bell, R. D. et al. Nature 485, 512–516 (2012).

  7. 7

    Fernández-Klett, F., Offenhauser, N., Dirnagl, U., Priller, J. & Lindauer, U. Proc. Natl Acad. Sci. USA 107, 22290–22295 (2010).

  8. 8

    Peppiatt, C. M., Howarth, C., Mobbs, P. & Attwell, D. Nature 443, 700–704 (2006).

  9. 9

    Cohen, Z., Molinatti, G. & Hamel, E. J. Cereb. Blood Flow Metab. 17, 894–904 (1997).

  10. 10

    Lindahl, P., Johansson, B. R., Levéen, P. & Betsholtz, C. Science 277, 242–245 (1997).

  11. 11

    Yemisci, M. et al. Nature Med. 15, 1031–1037 (2009).

  12. 12

    Vates, G. E., Takano, T., Zlokovic, B. & Nedergaard, M. Nature Med. 16, 959 (2010).

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Correspondence to Daniel M. Greif or Anne Eichmann.

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Greif, D., Eichmann, A. Brain vessels squeezed to death. Nature 508, 50–51 (2014). https://doi.org/10.1038/nature13217

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