Reynell, C; (2013) Identification and Functional Characterization of CNS Pericytes and the Role they Play in Neurovascular Coupling in Physiological and Pathological Conditions. Doctoral thesis , UCL (University College London).

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Abstract

Brain blood flow increases, evoked by neuronal activity, power neural computation and are the basis of BOLD functional imaging. However, it is controversial whether blood flow is controlled solely by arteriole smooth muscle, or also by capillary pericytes. The experimental work within this thesis examines capillary pericytes, and the role they play in neurovascular coupling in physiological and pathological conditions. I show that pericytes can be identified using several protein markers and that, using the same technique, pericytes can be distinguished from other perivascular cell types. I demonstrate that pericytes respond to the neurotransmitters noradrenaline and glutamate. Noradrenaline depolarizes pericytes and constricts capillaries, and this constriction reflects pericyte contraction while glutamate, mimicking neuronal activity, hyperpolarizes pericytes and dilates capillaries, and this dilation reflects pericyte relaxation. Glutamate-evoked dilation is mediated by prostaglandin E₂ or a related compound acting at EP4 receptors, but requires nitric oxide release to suppress synthesis of the vasoconstrictor 20-HETE. In pathology, I show that pericytes die when exposed to ischaemia. This may lead to pericytes irreversibly constricting capillaries and to damage of the blood-brain barrier. Pericyte death increases on reperfusion after ischaemia, and is reduced by block of glutamate receptors or Ca2+ removal, but not by scavenging reactive oxygen species. These data establish pericytes as active regulators of capillary tone and thus as potential regulators of brain blood flow. My data also suggest prevention of pericyte death as a strategy to reduce the long-lasting blood flow decrease which contributes to neuronal death after stroke. This thesis also contains a discussion of how energy supply to the brain alters with age, and how this may affect the BOLD signal.

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