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Review
. 2013 Sep 1;305(5):H609-19.
doi: 10.1152/ajpheart.00359.2013. Epub 2013 Jun 21.

Astrocyte regulation of cerebral vascular tone

Affiliations
Review

Astrocyte regulation of cerebral vascular tone

Jessica A Filosa et al. Am J Physiol Heart Circ Physiol. .

Abstract

Cerebral blood flow is controlled by two crucial processes, cerebral autoregulation (CA) and neurovascular coupling (NVC) or functional hyperemia. Whereas CA ensures constant blood flow over a wide range of systemic pressures, NVC ensures rapid spatial and temporal increases in cerebral blood flow in response to neuronal activation. The focus of this review is to discuss the cellular mechanisms by which astrocytes contribute to the regulation of vascular tone in terms of their participation in NVC and, to a lesser extent, CA. We discuss evidence for the various signaling modalities by which astrocytic activation leads to vasodilation and vasoconstriction of parenchymal arterioles. Moreover, we provide a rationale for the contribution of astrocytes to pressure-induced increases in vascular tone via the vasoconstrictor 20-HETE (a downstream metabolite of arachidonic acid). Along these lines, we highlight the importance of the transient receptor potential channel of the vanilloid family (TRPV4) as a key molecular determinant in the regulation of vascular tone in cerebral arterioles. Finally, we discuss current advances in the technical tools available to study NVC mechanisms in the brain as it relates to the participation of astrocytes.

Keywords: astrocytes; cerebral autoregulation; neurovascular coupling; parenchymal arteriole; vascular tone.

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Figures

Fig. 1.
Fig. 1.
Hypothetical illustration of the major cellular components comprising the neurovascular unit in the cerebral cortex. As pial arterioles penetrate the brain parenchyma, they gradually lose innervations from extracellular nerves originating from peripheral ganglia. The vascular tone of parenchymal arterioles is chiefly regulated by signals derived from neurons and astrocytes that encase much of the abluminal surface of the arterioles.
Fig. 2.
Fig. 2.
K+ signaling mechanisms at the neurovascular unit. Schematic representation of the signaling mechanism by which endothelial cell (EC) and astrocyte signaling induce membrane potential (Vm) hyperpolarization of vascular smooth muscle cells (VSMCs) and arteriole vasodilation. Shear stress or agonist-induced activation of G protein-coupled receptors (GPCR) increases Ca2+ in ECs via transient receptor potential (TRP) channel-dependent mechanisms resulting in the activation of intermediate conductance (IK) and small conductance (SK) potassium channels. The hyperpolarization mediated by these channels spreads to the VSMCs through myoendothelial gap junctions (MEGJ). Moreover, the resulting K+ efflux from ECs activates VSMC inwardly rectifying K+ channel (Kir) channels and the Na+/K+ pump inducing Vm hyperpolarization and closure of voltage-dependent calcium channels (VDCC), decreased intracellular Ca2+, and VSMC relaxation. On the other hand, glutamate released during neuronal activation binds to GPCRs on astrocytes, triggering an increase in Ca2+ that, in turn, activates large conductance Ca2+ activated potassium channels (BK) on astrocytic end feet (EF). Astrocytic BK channel activation causes potassium efflux into the perivascular space and, again, VSMC Kir channel activation followed by relaxation. TRP of the vanilloid family (TRPV4) channel activation has recently been shown to elicit increases in astrocytic EF Ca2+ as well. The intracellular Ca2+ increase in ECs and astrocytes also results in PLA2 activation, arachidonic acid (AA) metabolism, and the production/release of various vasoactive substances including epoxyeicosatrienoic acids (EETs), which in turn can modulate BK channels in astrocytes and vascular cells, further contributing to the regulation of vascular tone. TRPC1, transient receptor potential canonical-1.

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