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Review
, 100 (1), 307-17

Role of Astrocytes in Cerebrovascular Regulation

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Review

Role of Astrocytes in Cerebrovascular Regulation

Raymond C Koehler et al. J Appl Physiol (1985).

Abstract

Astrocytes send processes to synapses and blood vessels, communicate with other astrocytes through gap junctions and by release of ATP, and thus are an integral component of the neurovascular unit. Electrical field stimulations in brain slices demonstrate an increase in intracellular calcium in astrocyte cell bodies transmitted to perivascular end-feet, followed by a decrease in vascular smooth muscle calcium oscillations and arteriolar dilation. The increase in astrocyte calcium after neuronal activation is mediated, in part, by activation of metabotropic glutamate receptors. Calcium signaling in vitro can also be influenced by adenosine acting on A2B receptors and by epoxyeicosatrienoic acids (EETs) shown to be synthesized in astrocytes. Prostaglandins, EETs, arachidonic acid, and potassium ions are candidate mediators of communication between astrocyte end-feet and vascular smooth muscle. In vivo evidence supports a role for cyclooxygenase-2 metabolites, EETs, adenosine, and neuronally derived nitric oxide in the coupling of increased blood flow to increased neuronal activity. Combined inhibition of the EETs, nitric oxide, and adenosine pathways indicates that signaling is not by parallel, independent pathways. Indirect pharmacological results are consistent with astrocytes acting as intermediaries in neurovascular signaling within the neurovascular unit. For specific stimuli, astrocytes are also capable of transmitting signals to pial arterioles on the brain surface for ensuring adequate inflow pressure to parenchymal feeding arterioles. Therefore, evidence from brain slices and indirect evidence in vivo with pharmacological approaches suggest that astrocytes play a pivotal role in regulating the fundamental physiological response coupling dynamic changes in cerebral blood flow to neuronal synaptic activity. Future work using in vivo imaging and genetic manipulation will be required to provide more direct evidence for a role of astrocytes in neurovascular coupling.

Figures

Fig. 1
Fig. 1
Schematic diagram of tissue PO2 as a function of distance from a capillary at the downstream end of the O2-exchange site. A parabolic PO2 profile is used for illustrative purposes for the simplified case of O2 diffusion into a rectangular slab of tissue of infinite length and a homogeneous consumption of O2 (CMRO2) throughout the parenchyma (solid line at baseline CMRO2). If an increase in CMRO2 results in a proportional increase in blood flow, then there would be no change in fractional O2 extraction (E) and no change in end-capillary PO2. The increase in CMRO2 would then result in a steeper PO2 gradient to maintain the increased O2 flux and in a lower PO2 throughout the tissue, such that mitochondria at the greatest distance from a capillary would be at greater risk of inadequate O2 supply (dotted line). If blood flow increases by a greater percent than the increase in CMRO2, then there would be a decrease in E and an increase in end-capillary PO2. The increase in CMRO2 would still result in a steeper PO2 gradient throughout the tissue, but mitochondria at the greatest distance from a capillary would have less risk of inadequate O2 supply (dashed line).
Fig. 2
Fig. 2
Effect of different inhibitors applied to cortical surface on the cortical blood flow response to sensory activation plotted as a percentage of the control response in each experiment. A: reduction in the response to whisker stimulation with the nitric oxide synthase inhibitor Nω-nitro-L-arginine (L-NNA), the adenosine receptor antagonist theophylline, and combined L-NNA and theophylline [data adapted from Dirnagl et al. (26) and Lindauer et al. (63)]. B: reduction in the response to whisker response with the cyclooxygenase-2 (COX-2) inhibitor N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398) and in COX-2 null mice (COX-2 −/−) with and without NS-398 [data adapted from Niwa et al. (83)]. C: reduction in response to electrical foreleg stimulation with L-NNA, the epoxygenase inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH), and combined L-NNA and MS-PPOH [data adapted from Peng et al. (91)]. All inhibitors individually reduced the flow response to ~40–60% of the control response. Combining L-NNA with theophylline or MS-PPOH produced either a small or no additional inhibition, suggesting an interaction among these pathways.
Fig. 3
Fig. 3
Block diagram illustrating potential signaling pathways of neurovascular coupling and their interactions among neuronal, astrocyte, vascular smooth muscle, and endothelial compartments. Negative control pathways are indicated by dotted lines. cAMP, cyclic AMP; cGMP, cyclic GMP; CYP 4A, cytochrome P450 4A; EETs, epoxyeicosatrienoic acids; 20-HETE, 20-hydroxyeicosatetraenoic acid; IP3, inositol triphosphate; KCa, calcium-sensitive potassium channels; Kir, inward-rectifier potassium channel; mGluR, metabotropic glutamate receptor; NMDAR, N-methyl-D-aspartate receptor; NO, nitric oxide; NOS, nitric oxide synthase; PGs, prostaglandins; PLC, phospholipase C.

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