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Scientists Uncover Potential Key to Brain Blood-Flow Disorders

January 04, 2007

Scientists at the University of Vermont have clarified the cellular process responsible for signaling regional blood flow changes in the brain, thereby uncovering possible causes for such disorders as stroke, migraine, and Alzheimer's disease. The study was published November 1, 2006 in the prestigious journal Nature Neuroscience.

To function properly, the brain needs to receive an uninterrupted supply of oxygen and glucose, which is provided through an intricate network of blood vessels in the brain. Different parts of the brain are engaged by every activity, such as analytical thought, piano playing, seeing, hearing, walking, and these regions then require a rapid elevation of blood flow to meet the increased metabolic needs of the relevant brain cells (neurons). Though this cellular activity can be visualized in modern-day functional brain scans, the mechanisms by which these neurons signal blood vessels to dilate and increasing blood flow remain largely unknown, and are central to understanding brain function.

The diameter of blood vessels in the brain can be modulated by extracellular potassium, a common element present inside and outside all cells of the body. Such modulation of vessel diameter permits changes in blood flow to occur in the brain, as well as in other organs and tissues. With this knowledge, lead study author Mark Nelson, Ph.D., professor and chair of pharmacology at the University of Vermont, set out to determine whether the diameter of cerebral blood vessels in the brain could be modulated under physiological conditions by external potassium ions. To accomplish this, he and his research team studied the communication that takes place between neurons and blood vessels in mouse and rat brains.

The research team discovered early on that neuronal activity appeared to be communicated to the blood vessels through intermediary cells known as astrocytes. Astrocytes, which comprise about half the brain, had not been thought to play an active role in brain processes, and were thought to serve as the "glue" of the brain. One end of an individual astrocyte forms extensive contacts with thousands of neurons, while the other end surrounds and encases blood vessels. In this way, astrocytes are capable of integrating information from a large number of neurons and translating this information into distinct physiological outcomes, including modulation of blood flow.

In order to try and find out how neurons use astrocytes to communicate rapidly to blood vessels, the team of scientists at the University of Vermont employed highly advanced technologies to observe the movement of ions between the neuron, astrocyte and blood vessel. Using fluorescent dyes and high resolution microscopy, they detected a calcium wave that moves through the astrocyte from points of contacts with active neurons to the parts - called "endfeet" - which encase the blood vessels. The information from the active neuron is thus encoded as a calcium signal in the astrocyte. This increase in calcium at the endfeet activates a calcium-sensitive protein, known as a potassium (BK) channel, which permits potassium ions to pour out of the astrocytes onto the adjacent muscle cells in the brain artery. The authors showed that removing the BK channels, either by drugs or genetically, significantly reduced the dilation of the blood vessel in response to brain activity; hence the astrocytic BK channel is an important participant in the signaling mechanism.

The team next needed to uncover how the muscle cells responsible for determining blood flow in the blood vessel sense an increase in external potassium. To do this, Nelson and his colleagues focused on a potassium-sensitive protein expressed in smooth muscle cells called the inward rectifier potassium channel, which forms the contractile elements of blood vessels. When there is a small elevation of external potassium, the activity of these channels increases, causing smooth muscle cells to become less excitable, resulting in relaxation of the cells, dilation of vessels, and hence an increase in local blood flow. Similar to the BK channel, it was found that a reduction of inward rectifier channels prevented dilation of vessels in response to neuronal activity. These findings support the novel concept that precise and spatially localized release of potassium ions from astrocytes onto blood vessels mediates the rapid transmission of neuronal activity into regional increases in blood flow.

"This mechanism recapitulates many of the unique features of activity-induced cerebral blood flow changes measured in vivo, not the least of which is the rapid nature of these changes, which occur within 1-2 seconds of neuronal activity" said Nelson. "In addition, this mechanism places into a physiological context the well characterized responsiveness of the cerebral circulation to changes in extracellular potassium, and suggests that alterations in astrocytic BK channel or smooth muscle cell inward rectifier potassium channel function could contribute to cerebrovascular disorders including local cerebral ischemia, dementia and Alzheimer's disease."

This study suggests that these proteins may be novel targets to protect the brain from cerebrovascular disorders. In addition to Nelson, the research team included Jessica Filosa, Ph.D., postdoctoral fellow in pharmacology; Adrian Bonev, Ph.D., research assistant professor of pharmacology; Stephen Straub, Ph.D., postdoctoral fellow in pharmacology; Keith Wilkerson, Ph.D., postdoctoral fellow in pharmacology; and collaborators at Stanford University.

As a follow up to this work, Nelson and Straub published a study in the December 2006 issue of the Journal of General Physiology that investigated the spatial and temporal characteristics of the calcium signals within astrocytic endfeet, and defined the spatial context of vasoactive signals generated by endfeet. This study utilized the spatially and temporally-controlled photo-release of the intracellular calcium releasing messenger inositol trisphosphate within individual endfeet in brain to demonstrate that activation of a single endfoot is sufficient to induce local vasodilation of an adjacent blood vessel. This vasodilation was restricted to a short stretch of the vessel centered on the endfoot, suggesting that endfeet function as individual "vasoregulatory units" in the brain. One of many implications of this work is that any disruption of astrocytic function will compromise blood flow at critical times during brain activity.

This research was supported by grants from the National Institutes of Health National Heart, Lung, and Blood Institute, the American Heart Association, and the Totman Trust for Medical Research.

The University of Vermont