Sponsor: Maiken Nedergaard, MD, PhD Project Title: Dysregulation of functional hyperemia after subarachnoid hemorrhage

"Preliminary evidence suggests that astrocytes lose their normal ability to increase blood flow in specific regions of the brain as a function of neural activity (functional hyperemia). If this is true, and if we can find pharmacologic ways to restore this ability to coordinate functional hyperemia, it is possible that we will be able to better understand how SAH causes stroke, and how to prevent the devastating complication of aneurysm rupture," said Dr. Vates.

G. Edward Vates, MD, PhD

G. Edward Vates, MD, PhD, a native of Wilmington, Del., has been selected as one of four recipients of the 2006 Young Clinician Investigator Award. Dr. Vates is an assistant professor in the Department of Neurosurgery at the University of Rochester Medical School. He was a Fellow in cerebrovascular and skull base surgery and on staff at Brigham and Women's Hospital in Boston, Mass. from 2003 to 2005.

This award will enable Dr. Vates to pursue advanced research exploring brain mechanisms after subarachnoid hemorrhage (SAH), a deadly interruption of blood flow to the brain, which affects 30,000 Americans a year.

Mid-year Report by Dr. Vates

My grant proposal focused on the study of how astrocytes may cause disturbances in cerebral blood flow after subarachnoid hemorrhage (SAH). In order to determine if SAH causes astrocytes to lose their usual ability to vasodilate cerebral microvessels, I examined the brains of mice after causing SAH by injecting their own blood into the CSF in the cisterna magna. Unlike other studies where examinations of the effects of SAH are determined in brain slices, I was able to use a relatively new technique called two-photon laser scanning microscopy (LSM) to study astrocytes and microvessel in the living brain.

What my work has shows is that after SAH, astrocytes because reactive, sprouting multiple thickened processes and increasing the size of the processes that are directly applied to the outside of cerebral microvessels. In the brain of a mouse without SAH, erythrocytes circulate through capillaries swiftly and in an orderly fashion, like soldiers marching single-file
(see normal video). After SAH, however, the capillaries become irregular in caliber, and erythrocytes are suddenly caught in traffic jams throughout the cerebral microvessels
(see "SAH" video). In some cases, circulation continues but at half the normal pace; in other capillaries, however, circulation of blood cells is completely absent, although serum still appears to circulate, suggesting that neurons in these "ischemic" territories may be deprived of oxygen but still supplied with glucose and other compounds that could conceivably worsen hypoxic injury (due to absent erythrocytes).

Preliminary work using manipulation of the astrocytes by causing increased intracellular calcium (using an ultraviolet laser pulse to "uncage" calcium within the astrocyte) suggests that increased intracellular calcium does not elicit vasodilation after SAH; this is stark contrast to what is seen in

Fig. 11. 2-photon imaging of the cerebral vasculature (Texas Red-dextran, red) and Ca2+ (fluo-4/am, blue) after SAH. A Low power image of cortex (50 µm below pial surface) shows abnormal high baseline fluo-4 emission (most pronounced in the left side of the field. B A vessel in the left panel without constrictions. C A vessel in the right panel exhibits several small regions of vasoconstrictions (yellow arrowheads), which are never observed in control mice. D photolysis of caged Ca2+ fails to trigger vasodilation after SAH. The uncaging laser pulse (*) elicited an increase in cytosolic Ca2+, as indicated by the increase in fluo-4 within the targeted astrocyte endfoot, but the vessel lumen did not expand.

normal animals, and suggests that SAH causes astrocytes to lose the ability to regulate vasomotor tone at the microcirculatory level, resulting in increased, unopposed constrictor tone. More work needs to be done to confirm this finding, and to see what role other cells, such as pericytes or smooth muscle cells, may be playing at the microcirculatory level in the setting of SAH. Hopefully these studies will define new pathways for treating ischemia in the setting of SAH.

If you would like to learn more about neurosurgical research or to make a gift to NREF, visit our Web site at www.AANS.org/research or contact us at: (888)-566-AANS (2267).

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