Journal Article

Capillary pericytes regulate cerebral blood flow in health and disease

Hamilton, Nicola B., O’Farrell, Fergus M., Hall, Catherine N., Lauritzen, Martin, Reynell, Clare, Gesslein, Bodil, Buchan, Alastair M., Attwell, David, Mishra, Anusha, Sutherland, Brad A.

2014

Overview

Increases in brain blood flow, evoked by neuronal activity, power neural computation and form the basis of BOLD (blood-oxygen-level-dependent) functional imaging. Whether blood flow is controlled solely by arteriole smooth muscle, or also by capillary pericytes, is controversial. We demonstrate that neuronal activity and the neurotransmitter glutamate evoke the release of messengers that dilate capillaries by actively relaxing pericytes. Dilation is mediated by prostaglandin E 2 , but requires nitric oxide release to suppress vasoconstricting 20-HETE synthesis. In vivo , when sensory input increases blood flow, capillaries dilate before arterioles and are estimated to produce 84% of the blood flow increase. In pathology, ischaemia evokes capillary constriction by pericytes. We show that this is followed by pericyte death in rigor, which may irreversibly constrict capillaries and damage the blood–brain barrier. Thus, pericytes are major regulators of cerebral blood flow and initiators of functional imaging signals. Prevention of pericyte constriction and death may reduce the long-lasting blood flow decrease that damages neurons after stroke. Neuronal activity relaxes pericytes, leading to capillary dilation and increased blood flow, before arterioles dilate, suggesting that pericytes initiate blood-oxygen-level-dependent (BOLD) functional imaging signals; pericytes constrict and die in rigor in ischaemia, which will cause a long-lasting blood flow decrease after stroke, and damage the blood–brain barrier. Blood flow response to neural activity Cerebral blood flow dynamics have long been linked to neural activity, and form the basis of BOLD (blood-oxygen-level-dependent) functional imaging. But how such blood flow changes are mediated has remained controversial. Here, David Attwell and colleagues reveal how neuronal activity can hyperpolarize pericytes, leading to their relaxation and capillary dilation. Capillary dilation is responsible for 84% of the blood increase linked to neural activity, so irreversible capillary closure due to pericyte death during ischaemia can injure the blood–brain barrier and exacerbate injury. Pericyte death under pathological conditions can be reduced if glutamate receptor signalling is inhibited. This work suggests that pericytes are major regulators of cerebral blood flow and may initiate BOLD imaging signals.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 14/19 / 14/69 / 631/378/87 / 9/74 / Animals / Arterioles - physiology / Blood / Blood vessels / Blood-Brain Barrier - pathology / Blood-Brain Barrier - physiopathology / Brain Ischemia - pathology / Capillaries / Capillaries - cytology / Capillaries - drug effects / Cell Death / Cerebellum - blood supply / Cerebral circulation / Cerebral Cortex - blood supply / Cerebral Cortex - cytology / Cerebrovascular Circulation - drug effects / Cerebrovascular Circulation - physiology / Control / Dinoprostone - metabolism / Excitatory Amino Acid Antagonists - pharmacology / Female / Free radicals / Functional Neuroimaging / Glutamic Acid - pharmacology / Health aspects / Humanities and Social Sciences / Hydroxyeicosatetraenoic Acids - biosynthesis / In Vitro Techniques / Influence / Male / Mice / Mice, Inbred C57BL / multidisciplinary / Nitric oxide / Nitric Oxide - metabolism / Pericytes - cytology / Pericytes - drug effects / Pericytes - pathology / Pericytes - physiology / Rats / Rats, Sprague-Dawley / Rats, Wistar / Receptors, Glutamate - metabolism / Rodents / Science / Signal Transduction - drug effects / Stem cells / Stroke - pathology / Structure / Variance analysis / Vasoconstriction / Vasodilation - drug effects