The hemodynamic changes underlying the increases in blood flow are mediated by vasoactive agents Akt inhibitor with opposing vascular actions (vasodilatation or vasoconstriction), generated by synaptic activity, astrocytes, interneurons, and afferent projections from the basal forebrain and brainstem (Cauli and Hamel, 2010, Drake and Iadecola,

2007 and Kleinfeld et al., 2011). These highly coordinated signals converge on specific sites of the cerebrovascular network to shape the hemodynamic response to neural activation with a remarkable degree of spatial and temporal precision (Iadecola, 2004). Thus, the regional hemodynamic changes induced by activation are widely used to localize neuronal activity in the living brain using functional imaging (Attwell and Iadecola, 2002). Like in other organs, endothelial cells regulate vascular tone by releasing vasoactive factors in response to chemical AUY-922 clinical trial signals, e.g., transmitters (Andresen et al., 2006), or mechanical forces, e.g., shear stress (Ando and Yamamoto, 2013). Unlike other organs, cerebral endothelial cells in most brain regions are adjoined by intricate junctional complexes formed by occludins and claudins (tight junctions) that prevent the bidirectional exchange of hydrophilic

substances between blood the brain, a key feature of the BBB (Dyrna et al., 2013). Rather, specialized transport proteins on the endothelial cell membrane control the traffic of solutes in and out of the brain. For example, GLUT1 and aminoacid transporters regulate the

transfer of glucose and aminoacids into the brain, whereas “efflux transporters,” oxyclozanide such as LRP-1, ABC transporters, and others, remove drugs and metabolic by-products from the brain, including Aβ and lactate (Neuwelt et al., 2011). Vascular smooth muscle cells, owing to their ability to constrict when intravascular pressure increases (myogenic tone), adjust vascular tone in response to changes in arterial pressure to maintain CBF relatively constant within a range of pressures (cerebrovascular autoregulation) (Cipolla, 2009). Autoregulation protects cerebral blood vessels from the wide swings in arterial pressure associated with the activities of daily living and provides a stabile CBF baseline on which the dynamic changes induced by neurovascular coupling and endothelium are superimposed. These neurovascular control mechanisms work in concert to assure that the brain receives sufficient blood flow to meet the metabolic needs of its active cellular constituents. Neurons, astrocytes, oligodendrocytes, and vascular and perivascular cells are in state of close trophic and metabolic codependence that plays a defining role in brain development, function, and reaction to injury.