Tone-dependent vascular responses to astrocyte-derived signals

Department of Psychiatry, College of Medicine, University of Cincinnati, Cincinnati, Ohio Submitted 13 December 2007 ; accepted in final form 30 April 2008 A growing number of studies support an important contribution of astrocytes to neurovascular coupling, i.e., the phenomenon by which variations in neuronal activity trigger localized changes in blood flow that serve to match the metabolic demands of neurons. However, since both constriction and dilations have been observed in brain parenchymal arterioles upon astrocyte stimulation, the specific influences of these cells on the vasculature remain unclear. Using acute brain slices, we present evidence showing that the specific degree of constriction of rat cortical arterioles (vascular tone) is a key determinant of the magnitude and polarity of the diameter changes elicited by signals associated with neurovascular coupling. Thus elevation of extracellular K + concentration, stimulation of metabotropic glutamate receptors (mGluR), or 11,12-epoxyeicosatrienoic acid application all elicited vascular responses that were affected by the particular resting arteriolar tone. Interestingly, the data suggest that the extent and/or polarity of the vascular responses are influenced by a delimited set point centered between 30 and 40% tone. In addition, we report that distinct, tone-dependent effects on arteriolar diameter occur upon stimulation of mGluR during inhibition of enzymes of the arachidonic acid pathway [i.e., phospholipase A 2 , cytochrome P -450 (CYP) -hydroxylase, CYP epoxygenase, and cycloxygenase-1]. Our findings may reconcile previous evidence in which direct astrocytic stimulation elicited either vasoconstrictions or vasodilations and also suggest the novel concept that, in addition to participating in functional hyperemia, astrocyte-derived signals play a role in adjusting vascular tone to a range where dilator responses are optimal. potassium; glutamate; epoxyeicosatrienoic acid; glia; neurovascular coupling Address for reprint requests and other correspondence: J. A. Filosa, Dept. of Psychiatry, College of Medicine, Univ. of Cincinnati, 2170 E. Galbraith Rd. (239-A), Cincinnati, OH (e-mail: jessica.filosa{at}uc.edu )