Bidirectional control of CNS capillary diameter by pericytes

Abstract

Non-invasive imaging techniques that reveal those parts of the brain that are active by detecting the increased blood flow that supplies extra glucose and oxygen to active nerve cells. Until now it was assumed that blood flow is controlled by the contraction of smooth muscle around large blood vessels called arterioles. Now an additional level of blood flow control has been discovered, downstream of arterioles. This control is exerted by the pericytes, small cells that wrap around the capillaries close to active nerve cells. The pericytes, that act by squeezing the capillary to reduce blood flow though it, are likely to contribute to the signals detected in brain imaging techniques, and could also provide a target for therapy in disorders of brain blood flow. Neural activity increases local blood flow in the central nervous system (CNS), which is the basis of BOLD (blood oxygen level dependent) and PET (positron emission tomography) functional imaging techniques1,2,3. Blood flow is assumed to be regulated by precapillary arterioles, because capillaries lack smooth muscle. However, most (65%) noradrenergic innervation of CNS blood vessels terminates near capillaries rather than arterioles4, and in muscle and brain a dilatory signal propagates from vessels near metabolically active cells to precapillary arterioles5,6, suggesting that blood flow control is initiated in capillaries. Pericytes, which are apposed to CNS capillaries and contain contractile proteins7, could initiate such signalling. Here we show that pericytes can control capillary diameter in whole retina and cerebellar slices. Electrical stimulation of retinal pericytes evoked a localized capillary constriction, which propagated at ∼2 µm s-1 to constrict distant pericytes. Superfused ATP in retina or noradrenaline in cerebellum resulted in constriction of capillaries by pericytes, and glutamate reversed the constriction produced by noradrenaline. Electrical stimulation or puffing GABA (γ-amino butyric acid) receptor blockers in the inner retina also evoked pericyte constriction. In simulated ischaemia, some pericytes constricted capillaries. Pericytes are probably modulators of blood flow in response to changes in neural activity, which may contribute to functional imaging signals and to CNS vascular disease.