Review
Purinergic mechanisms in gliovascular coupling

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Abstract

Regional elevations in cerebral blood flow (CBF) often occur in response to localized increases in cerebral neuronal activity. An ever expanding literature has linked this neurovascular coupling process to specific signaling pathways involving neuronal synapses, astrocytes and cerebral arteries and arterioles. Collectively, these structures are termed the “neurovascular unit” (NVU). Astrocytes are thought to be the cornerstone of the NVU. Thus, not only do astrocytes “detect” increased synaptic activity, they can transmit that information to proximal and remote astrocytic sites often through a Ca2+- and ATP-related signaling process. At the vascular end of the NVU, a Ca2+-dependent formation and release of vasodilators, or substances linked to vasodilation, can occur. The latter category includes ATP, which upon its appearance in the extracellular compartment, can be rapidly converted to the potent vasodilator, adenosine, via the action of ecto-nucleotidases. In the present review, we give consideration to experimental model-specific variations in purinergic influences on gliovascular signaling mechanisms, focusing on the cerebral cortex. In that discussion, we compare findings obtained using in vitro (rodent brain slice) models and multiple in vivo models (2-photon imaging; somatosensory stimulation-evoked cortical hyperemia; and sciatic nerve stimulation-evoked pial arteriolar dilation). Additional attention is given to the importance of upstream (remote) vasodilation; the key role played by extracellular ATP hydrolysis (via ecto-nucleotidases) in gliovascular coupling; and interactions among multiple signaling pathways.

Introduction

Coupling between neuronal activity and blood flow is fundamental to brain function. When a specific brain region is activated, cerebral blood flow (CBF) increases in a temporally and spatially coordinated manner. At the core of the coupling process is the neurovascular unit (NVU). In the context of CBF regulation, the three key components of the NVU are neurons, astrocytes, and arteries/arterioles. The general organization of the NVU reflects its function. That is, on one end of the structure, astrocytic endfeet extensively ensheath cerebral microvessels, such as arterioles. On the other end, astrocytes contact both pre- and post-synaptic elements (the “tripartite” synapse—see Ref. [1]). The latter arrangement permits astrocytes to “sample” synaptic function. However, the NVU, and its ability to couple blood flow to synaptic activity, is far more complex than an organization consisting of “one synapse-one astrocyte-one arteriole”. In fact, astrocytes are thought to be arranged in physically non-overlapping domains [2]. As such, the astrocyte in each domain can have multiple contacts with neuronal synapses, with more than 105 (rodents) or 106 (humans) synaptic contacts per domain, in addition to an indeterminate number of arteriolar contacts. Furthermore, increased synaptic activity may promote vasodilation that can occur within a single astrocytic domain (local parenchymal arteriolar dilation), or may involve multiple domains resulting in upstream or “remote” vasodilation. Another regulatory function arising from remote astrocytic signaling is heterosynaptic modulation. Related to the common theme of this special issue, “Purinergic Signaling in Neurones and Glia”, purinergic factors play key roles in this remote signaling process, irrespective of whether the distal target of the astrocytic signaling conduit is an arteriole or a synapse [3] (see also Fig. 1).

Section snippets

Signaling mechanisms within the NVU

Multiple mechanisms have been linked to astrocytes in their capacity to orchestrate cerebral vasodilation during increased synaptic activity (reviewed in Refs. [2], [4], [5]). Vasodilation in response to enhanced synaptic activity can be attributed, either directly or indirectly, to release of paracrine substances from astrocytes arising in response to transient elevations in astrocyte intracellular Ca2+ concentrations. Those Ca2+-dependent paracrine substances have been found to include

In vitro models: acute brain slice

The acute cortical brain slice often has been used in studies examining neurovascular coupling. Despite their limitations (reviewed in Ref. [12]), much useful information has been derived using slice preparations. Slice studies most commonly involve examinations of the direct influence of astrocytes on intraparenchymal arteriolar diameters. In many cases, this entails “endfoot delimited” astrocytic signaling elicited by photolytic uncaging of endfoot Ca2+ [13] or inositol trisphosphate (IP3),

In vivo models: two-photon imaging

Takano et al. [22] employed in vivo two-photon laser-scanning microscopy in anesthetized mice to explore the vascular effects of Ca2+ uncaging in astrocyte endfeet directly adjacent to cortical penetrating arterioles. Within seconds of the photolytic event, arteriolar dilation was observed. The only agents which prevented the vasodilating response were blockers of arachidonic acid synthesis and COX-1, consistent with a primary role for arachidonic acid-derived PGE2. In contradistinction with

Model for upstream vasodilation and gliovascular signaling

Upstream vasodilation is an important component of neurovascular coupling. One example of remote, upstream dilation would be the pial arteriolar dilation that occurs in the hindlimb region of the cerebral cortex during sciatic nerve stimulation (SNS) [39], [40]. Pial arterioles represent the upstream segments of the parenchymal arterioles that lie in the vicinity of activated synapses [9]. In recent publications (e.g., Ref. [40]), we reported astrocytes were a major conduit for transmitting

Summary

Adenosine triphosphate plays a central role in coupling increased synaptic activity in the brain to increases in CBF. One key aspect of that signaling is inter-astrocytic communication, where ATP released from one astrocyte can activate metabotropic purinergic receptors on neighboring astrocytes, thereby promoting IP3-mediated Ca2+ release from cellular stores. Through repeating that process, or via diffusion of IP3 and Ca2+ through inter-astrocytic (gap junction) channels, local and remote

Acknowledgments

This work was supported by a grant from the American Heart Association (AHA-0635337N) and National Institutes of Health Grants, HL-088259 and NS-063279.

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