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Symposium Reports |
1 Department of Psychiatry, University of Cincinnati, 2170 East Galbraith Road, Room 239-A, Cincinnati, OH 45237, USA
Abstract
Normal brain function requires proper supply of oxygen and glucose in a timely and local manner. This is achieved through an orchestrated intercellular communication between neurones, astrocytes and microvessels that results in a rapid and restricted increase in cerebral blood flow, a process known as neurovascular coupling. Astrocytic end-feet make close contacts with neuronal synapses and blood vessels and, given their ability to release vasoactive signals following neuronal activation, have been recognized as key intermediaries in the neurovascular response. Both dilating and constricting signals appear to be released from astrocytes upon increases in intracellular Ca2+ concentration, and both dilatation and constriction of brain vessels have been observed in previous studies. In this article, we discuss the various astrocyte-derived vasodilating and vasoconstricting signals, their interactions and effects on astrocytes and vascular smooth muscle cells, and suggest the importance of the intrinsic properties of the latter cell type on the overall neurovascular response. We present a working model in which the rise in astrocytic Ca2+ following neuronal activation leads not only to the rapid activation of calcium-activated K+ channels in astrocytic end-feet, but also to their modulation by metabolites of the arachidonic acid pathway, which in general have been proposed to act on vascular smooth muscle cells rather than on astrocytes. We propose that this latter mechanism may in turn modulate K+ signalling from astrocytes to smooth muscle cells, influencing the overall effects of the vasodilating and vasoconstricting signals released during neuronal activation.
(Received 16 March 2007;
accepted after revision 4 May 2007; first published online 4 May 2007)
Corresponding author J. A. Filosa: Department of Psychiatry, University of Cincinnati, 2170 East Galbraith Road, Room 239-A, Cincinnati, OH 45237, USA. Email: jessica.filosa{at}uc.edu
Extrinsic and intrinsic innervation of brain vasculature
The cerebral circulation can be divided into extracerebral and intracerebral blood vessels. The primary extracerebral blood vessels are the internal carotid and the vertebral–basilar system, which communicate to form the circle of Willis. Branches from the circle of Willis give rise to resistance arterioles, the pial vessels, which penetrate the brain parenchyma at right angles as penetrating or parenchymal arterioles (Edvinsson & MacKenzie, 2002). The neurovascular control of the cerebral circulation varies depending on the location and caliber of the vessels. In general, extracerebral vessels are innervated by peripheral nerves (extrinsic innervation) of sympathetic, parasympathetic and sensory origin (Bleys & Cowen, 2001). Parenchymal microvessels, in contrast, are primarily regulated by afferents from subcortical pathways, local interneurones and neuronal terminals from a central origin (intrinsic innervation; Hamel, 2006).
In addition, parenchymal arterioles are also regulated by astrocytes, which fully encase the vasculature with highly specialized structures called end-feet (Peters et al. 1991; Kacem et al. 1998). Owing to the tight physical contacts between neuronal and astrocytic processes, it is likely that in addition to the direct action of neurone-derived signals on vascular cells, these signals may also modulate vascular function indirectly by influencing astrocytic activity. While the remainder of this report will focus on astrocyte-induced vascular changes, we refer the reader to an excellent review by Edith Hamel on the control of cerebrovascular tone by intrinsic and extrinsic neuronal pathways (Hamel, 2006).
Local regulation of blood flow in the brain
Investigations in the late 1800s (Mosso, 1880; Roy & Sherrington, 1890) made evident that the brain possesses mechanisms by which increased neuronal activity is matched by a rapid and regional increase in blood supply, a phenomenon known today as ‘functional hyperaemia’. The release of vasoactive agents into the extracellular space was proposed to be the underlying mechanism (Roy & Sherrington, 1890). A problematic aspect of this ‘metabolic hypothesis’, however, is that simple diffusion of neurone-derived vasoactive substances in the brain parenchyma may not be rapid enough, hence their concentration near the vessels may not be sufficient to produce a timely and adequate vascular response. Instead, the direct action of signals released from neurones and/or astrocytes onto vascular cells within specialized contact areas, such as the spaces between astrocytic end-feet or neuronal varicosities and the vessel wall, appears more effective in eliciting such response.
There have been several anatomical and functional studies linking direct neuronal stimulation with vascular responses. Krimer and colleagues showed that central dopaminergic neurones make close contacts with the basal lamina of arterioles and with astrocytic end-feet, and that microinjection of dopamine results in pronounced constriction of cerebral microvessels (Krimer et al. 1998). In contrast, vasodilatation of cortical arterioles has been associated with the activation of cholinergic fibres (Vaucher & Hamel, 1995; Vaucher et al. 1997) and nitric oxide (NO)-containing neurones (Tong & Hamel, 2000). Cauli et al. (2004) showed that stimulation of single interneurones expressing vasoactive intestinal peptide or NO synthase mediated arteriolar dilatation, whereas stimulation of interneurones expressing somatostatin produced constriction. While these studies provided evidence for direct neurovascular communication, others have also suggested that some neurone-derived signals may act on the vasculature via astrocytic stimulation. For example, while parenchymal arterioles receive limited noradrenergic innervation, and direct stimulation with noradrenaline (NA) does not have significant effects on vasomotor activity (Dacey & Duling, 1984; Cipolla et al. 2004), NA-containing terminals make extensive contacts with astrocytes (Cohen et al. 1997), and constriction of blood vessels has been shown to occur upon increases in intracellular Ca2+ concentration ([Ca2+]i) in astrocytic end-feet exposed to NA (Mulligan & MacVicar, 2004).
Neurovascular coupling (NVC): the glial factor
Astrocytes, which in fact make up about half of the brain volume, were regarded for a long time as rather simple supporting cells for neurones. In the last decades, however, there has been a significant amount of evidence suggesting other functional roles in both physiological and pathological conditions (Haydon & Carmignoto, 2006). In addition to their participation in neurotransmitter and ion homeostasis, it is now clear that astrocytes have a prominent role as mediators of vasomotor activity. By sending projections to both the synapse and the blood vessels, they are in a unique anatomical position to sense and modulate synaptic activity, as envisioned in the ‘tripartite synapse model’ (Araque et al. 1999), and to influence regional blood flow accordingly (Simard et al. 2003; Filosa et al. 2006; Metea & Newman, 2006; Takano et al. 2006). The recognition of this phenomenon has led to intensive research focused on the mechanisms that define the participation of glial cells in NVC in the brain.
Astrocytes respond to an increase in synaptic activity with a rise in [Ca2+]i, mediated largely by activation of metabotropic glutamate receptors (Cornell-Bell et al. 1990; Zonta et al. 2003). If synaptic strength is high, it will trigger the propagation of a Ca2+ wave that travels towards their end-feet processes making contact with nearby microvessels (Zonta et al. 2003; Filosa et al. 2004; Straub et al. 2006). This step appears to be critical for astrocyte-induced vascular responses. To date, this observation has been associated predominantly with vasodilator responses, by both in vivo (Takano et al. 2006) and in vitro studies (Zonta et al. 2003; Filosa et al. 2006; Metea & Newman, 2006; Blanco & Filosa, 2006), but also with vasoconstrictor responses, by in vitro studies (Mulligan & MacVicar, 2004; Blanco & Filosa, 2006). While differences in the type of responses may be attributed to the limitations of the in vitro brain slice preparation (namely the lack of intraluminal pressure and shear stress), it is also possible that these limitations have unmasked important physiological features of NVC, such as the ability of astrocytes to constrict blood vessels. Clearly, more studies are needed to enable understanding of the precise mechanisms underlying astrocyte-induced vascular responses; a fundamental question still to be addressed is whether alterations in the properties of the vasculature itself can account for differences in the types of responses observed following neuronal and glial activation. We have started to address this important question and have found that, when challenged with the same vasodilating stimulus (i.e modest elevation in extracellular K+), the magnitude of the vascular response is affected by the resting tone of the arteriole (Unpublished observation) so that greater dilatations are seen with increasing levels of preconstriction (Unpublished observation). Based on these data, and on previous observations where, in response to astrocytic stimulation, non-preconstricted vessels constricted (Mulligan & MacVicar, 2004) and preconstricted vessels dilated (Zonta et al. 2003; Mulligan & MacVicar, 2004), it is tempting to speculate that while astrocytic stimulation can induce both dilatations and constrictions, the ultimate determinant of the particular type of vascular response arises from the vascular cells (Peppiatt & Attwell, 2004).
To date, a number of astrocyte-derived vasoactive signals have been defined. Among these are NO, several arachidonic acid (AA) metabolites [prostacyclins, prostaglandins (PGs), epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE)], adenosine and ATP (Girouard & Iadecola, 2006; Koehler et al. 2006). In spite of the mounting evidence supporting a role for astrocytes in mediating changes in arteriolar tone, the specific actions of each vasoactive agent, as well as the temporal and spatial conditions determining their release, remain little understood. A common denominator in the production and release of such mediators is the rise in astrocytic [Ca2+]i. As suggested by studies in cultured astrocytes, however, in principle both vasodilators (e.g. NO, ATP, PGE2 and EETs; Guthrie et al. 1999; Murphy, 2000; Zonta et al. 2003) and vasoconstrictors (e.g. 20-HETE, PGF2
, thromboxane A2 and endothelins; Pearce et al. 1989; MacCumber et al. 1990; Staub et al. 1995; Nithipatikom et al. 2001) can be produced and eventually released upon such [Ca2+]i increase. Thus, the question arises of what determines whether the vessel dilates or constricts? One possibility is that the specific production and release of a given vasoactive metabolite is determined by the characteristics of the astrocytic Ca2+ signalling response (rate of increase, amplitude, localization, pattern, etc.). For example, using liquid chromatographic-electrospray ionization-mass spectrometry, Nithipatikom et al. (2001) reported the production of both EETs and 20-HETE in cultured astrocytes. However, stimulation with 300 µM L-glutamate increased the concentration of EETs within the cells without inducing significant changes in 20-HETE levels, suggesting that differential activation of vasoactive pathways may occur in glia in response to glutamate (Nithipatikom et al. 2001). Alternatively, it is possible that astrocytes release both dilating and constricting signals into the perivascular space, and the overall balance between them, as well as the responsiveness of arteriolar smooth muscle cells, defines the type of vascular response.
Temporal control of vascular tone: chemical versus electrical signalling
In general, two kinds of glia-related signals can be identified as possible modulators of arteriolar diameter, hence blood flow: biochemical signals, comprising mainly, but not exclusively, metabolites of AA; and an ‘electric’ signal (inasmuch as it causes direct membrane potential changes), represented by K+ ions. While chemical signals are well suited to maintain changes in vessel tone in response to sustained neuronal activation, K+ fluxes seem more appropriate to elicit rapid vasomotor responses following neuronal activation.
K+ signalling at the gliovascular interface
It has long been recognized that increases in extracellular K+ concentration ([K+]o) can lead to vasorelaxation and that this response could be explained by the activation of Na+, K+-ATPase, inwardly rectifying K+ (Kir) channels, or both, depending on the vascular bed studied and the magnitude of the [K+]o elevation (Toda, 1974; Edwards et al. 1988; Edwards & Hirst, 1988; McCarron & Halpern, 1990; Quayle et al. 1993; Knot et al. 1996; Horiuchi et al. 2002). While the vasodilatory effects of K+ in the extracerebral circulation have been documented (McCarron & Halpern, 1990; Knot et al. 1996), direct evidence for the mechanisms underlying this phenomenon in parenchymal arterioles was until recently not available. Studies by us and others have proposed that the release of K+ ions from astrocytic end-feet and the subsequent activation of Kir channels expressed on vascular smooth muscle cells (VSMC) constitutes an effective mechanism leading to the rapid dilatation of parenchymal arterioles (Filosa et al. 2006). This hypothesis stems from early observations suggesting that the local release of K+ from astrocytic end-feet, during spatial K+ buffering, could also act as a potential signal leading to NVC in the retina (Paulson & Newman, 1987).
Astrocytic processes exhibit a heterogeneous distribution of K+ channels along their membrane, with high densities in areas adjacent to synapses and vascular elements (Newman, 1984; Brew et al. 1986). Key to our model of K+-mediated NVC is the high expression of large-conductance, voltage-dependent, Ca2+-activated K+ channels (BK channels) in astrocytic end-feet processes (Price et al. 2002). We propose that activation of these BK channels following neurotransmitter-induced [Ca2+]i increases would result in rapid efflux of K+ into the perivascular space, activating Kir channels in VSMC and inducing membrane hyperpolarization and vasodilatation of parenchymal arterioles (Fig. 1). Consistent with the idea that functional hyperaemia is a fast response, electrical stimulation of neurones resulted in rapid (< 2 s) dilatation of parenchymal arterioles, a response that was significantly and similarly attenuated in the presence of either BK or Kir channel blockers. The electrophysiological bases of these experimental results were further addressed through electrophysiological recordings of BK (in astrocytic end-feet) and Kir channel currents (in VSMC) in rat cortical brain slices. Iberiotoxin-sensitive currents constituted 
30% of macroscopic outward currents elicited in astrocytic end-feet processes. Moreover, neuronal stimulation was associated with the rapid efflux of K+ from BK channels expressed on astrocytic end-feet, as evidenced by a 160-fold increase in channel open probability (Filosa et al. 2006). In contrast, VSMC exhibited classic characteristics of Kir currents, such as membrane potential hyperpolarization and a rightward shift in the current–voltage curve with increasing concentrations of [K+]o, high sensitivity to external barium ions and strong rectification (Filosa et al. 2006).
To confirm the involvement of Ca2+ signalling in the hyperaemic response, intracellular Ca2+ transients in both astrocytes and VSMC were simultaneously monitored following neuronal stimulation. It was found that a rise in astrocytic end-feet [Ca2+] preceded a decrease in oscillatory intracellular Ca2+ activity in VSMC, an event associated with arteriolar dilatation (Filosa et al. 2004, 2006). This response was absent in mice lacking functional BK channels (Filosa et al. 2006). Importantly, astrocytic Ca2+ surges were significantly reduced by blocking synaptic activity with tetrodotoxin, while Ca2+ oscillations in VSMC were not, confirming neurone-to-glia communication (Filosa et al. 2004).
While our study clearly showed the importance of K+ signalling in NVC, it certainly does not rule out other signals and mechanisms. For example, while BK channel opening can mediate the rapid efflux of K+ and cause vasodilatation, there is firm evidence suggesting that AA metabolites interact with these channels, either in astrocytes or in VSMC, and have a significant effect on the dynamics of the neurovascular response under physiological and pathological conditions. For example, while EETs have been shown to induce vasodilatation via BK channel activation in VSMC (Gebremedhin et al. 1992; Campbell et al. 1996), recent studies suggest they may also modulate Ca2+-activated K+ channels in cultured hipoccampal astrocytes (Gebremedhin et al. 2003). Yamaura et al. (2006) recently demonstrated that the open probability of these channels was increased by exogenous application of 11,12-EET, possibly acting via a cytosolic intermediate. In accordance with these observations, we have evidence that exogenous EETs not only increased outward currents in native cortical astrocytes but also significantly increased [Ca2+]i in astrocytic end-feet (Blanco et al. 2007), where a high density of BK channels is known to exist (Price et al. 2002). These observations strongly suggest that in addition to having direct vascular effects, AA metabolites may also modulate the strength and timing of K+ signalling at the gliovascular interface. By modulating BK channel activation, EETs may prolong BK channel opening and thereby favour a larger efflux of K+ ions into the perivascular space. While this mechanism could result in the maintenance of the vasodilatory response, it is likely that a controlling mechanism exists, since excessive K+ efflux would lead to VSMC depolarization and arteriolar vasoconstriction.
In conclusion, our experimental data strongly support an important role for K+ ions in NVC in the brain. We propose that the concerted action of K+ ions and AA metabolites is largely responsible for the well-synchronized communication between active neurones, glial cells and cerebral blood vessels. Future studies addressing the intrinsic properties of the vascular cells and their modulation by these signalling mechanisms are needed to permit better understanding of the basis of functional hyperaemia in health and disease.
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Ackowledgements
This report was supported by funding from the American Heart Association, Science Development Grant (no. 0535231N) to J.A.F.
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