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Review
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The Role of Endothelial Ca 2+ Signaling in Neurovascular Coupling: A View From the Lumen

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Review

The Role of Endothelial Ca 2+ Signaling in Neurovascular Coupling: A View From the Lumen

Germano Guerra et al. Int J Mol Sci.

Abstract

Background: Neurovascular coupling (NVC) is the mechanism whereby an increase in neuronal activity (NA) leads to local elevation in cerebral blood flow (CBF) to match the metabolic requirements of firing neurons. Following synaptic activity, an increase in neuronal and/or astrocyte Ca2+ concentration leads to the synthesis of multiple vasoactive messengers. Curiously, the role of endothelial Ca2+ signaling in NVC has been rather neglected, although endothelial cells are known to control the vascular tone in a Ca2+-dependent manner throughout peripheral vasculature.

Methods: We analyzed the literature in search of the most recent updates on the potential role of endothelial Ca2+ signaling in NVC.

Results: We found that several neurotransmitters (i.e., glutamate and acetylcholine) and neuromodulators (e.g., ATP) can induce dilation of cerebral vessels by inducing an increase in endothelial Ca2+ concentration. This, in turn, results in nitric oxide or prostaglandin E2 release or activate intermediate and small-conductance Ca2+-activated K⁺ channels, which are responsible for endothelial-dependent hyperpolarization (EDH). In addition, brain endothelial cells express multiple transient receptor potential (TRP) channels (i.e., TRPC3, TRPV3, TRPV4, TRPA1), which induce vasodilation by activating EDH.

Conclusions: It is possible to conclude that endothelial Ca2+ signaling is an emerging pathway in the control of NVC.

Keywords: ATP; Ca2+ signaling; TRP channels; acetylcholine; brain endothelial cells; endothelial-dependent hyperpolarization; glutamate; neuronal activity; neurovascular coupling; nitric oxide.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cellular composition of the neurovascular unit. The vascular wall presents a different structure in arterioles and capillaries, which control the local supply of cerebral blood. Smooth muscle cells form one or more continuous layers around arterioles and change in their contractile state determine vessel diameter and regulate blood perfusion. Capillary diameter is regulated by contractile pericytes, which extend longitudinally and circumferentially along the capillary wall. Astrocyte end feet envelope arterioles and capillaries and are able to release vasoactive mediators, which regulate the contractile state of smooth muscle cells (arterioles) and pericytes (capillary) in response to neuronal activity.
Figure 2
Figure 2
The mechanisms by which neurons and astrocytes stimulate arteriole and capillary dilation in response to synaptic activity. Synaptic activity increases intracellular Ca2+ levels within the postsynaptic neuron by stimulating metabotropic G-protein-coupled receptors (GPCRs), ionotropic receptors (e.g., NMDARs) or L-type voltage-operated Ca2+ channels (VOCs). This increase in [Ca2+]i leads to the synthesis of NO and PGE2, which may relax both smooth muscle cells (arterioles) and pericytes (capillaries). Synaptically-released neurotransmitters may also increase [Ca2+]i in perisynaptic astrocytes, thereby triggering NO release and PGE2/EET production. AA, which may be synthesized by PLA2 in both neurons and astrocytes, may be converted in the vasoconstricting factor, 20-HETE, in perivascular cells. Abbreviations: 20-HETE: 20-hydroxyeicosatetraenoic acid; AA: arachidonic acid; COX1: cyclooxygenase 1; COX2: cyclooxygenase 2; EETs: epoxyeicosatrienoic acids; GPCRs; G-protein-coupled receptors; InsP3: inositol-1,4,5-trisphosphate; KCa: Ca2+-activated intermediate and small conductance K+ channels; NO: nitric oxide; nNOS: neuronal NO synthase; P450: cytochrome P450; PGE2: prostaglandin E2; PLA2: phospholipase A2; PLD2: phospholipase D2; VOCs: L-type voltage-operated Ca2+ channels.
Figure 3
Figure 3
The Ca2+ signaling toolkit in brain microvascular endothelial cells. There is scarce information available regarding the molecular components of the Ca2+ signaling toolkit in brain microvascular endothelial cells. A recent investigation, however, provided a thorough characterization of the Ca2+ machinery in bEND5 cells [76], which represent an established mouse brain microvascular endothelial cell line. Further information was obtained by the analysis of endothelial Ca2+ signals in rodent parenchymal arterioles and in the human hCMEC/D3 cell line. Extracellular autacoids bind to specific G-protein-coupled receptors, such as M-AchRs and P2Y1 receptors, thereby activating PLCβ, which in turn cleaves PIP2 into InsP3 and DAG. InsP3 triggers ER-dependent Ca2+ releasing by gating InsP3Rs, while DAG could activate TRPC3. The InsP3-dependent drop in ER Ca2+ levels induces SOCE, which is mediated by the interaction between Stim1 and Orai2 in bEND5 cells. Moreover, extracellular Ca2+ entry may occur through TRPV3, TRPV4 and TRPA1, which are coupled to either eNOS or EDH [77,78]. Finally, brain microvascular endothelial cells may express Ca2+-permeable ionotropic receptors, such as NMDARs and P2X7 receptors. The elevation in [Ca2+]i decays to the baseline via the concerted interaction between SERCA and PMCA pumps, as well as through NCX [72,79,80]. Abbreviations: InsP3, inositol-1,4,5-trisphosphate; DAG, diacylglycerol; InsP3Rs, InsP3 receptors; NCX, Na+–Ca2+ exchanger; PMCA, plasma membrane Ca2+ ATPase; PIP2, phosphatidylinositol-4,5-bisphosphate; PLCβ, phospholipase Cβ; SERCA, sarco-endoplasmic reticulum Ca2+-ATPase. The thicker line connecting PIP2 to InsP3 indicates a high amount of second messenger produced upon PLCβ activation.
Figure 4
Figure 4
Ca2+-regulated endothelium-dependent vasodilation. Agonists-induced InsP3-dependent ER Ca2+ depletion in vascular endothelial cells leads to store-operated Ca2+ entry (SOCE). SOCE is tightly coupled to eNOS, thereby triggering robust NO release. NO, in turn, diffuses towards adjacent vascular smooth muscle cells (VSMCs) at myo-endothelial projections and activates soluble guanylyl cyclase (sGC) to induce vasorelaxation. Extracellular agonists may also activate TRP channels (e.g., TRPC3, TRPV3, TRPV4 and TRPA1), which is preferentially coupled to Ca2+-activated K+ channels (KCa), such as IKCa and SKCa. Endothelial hyperpolarization spreads through myo-endothelial gap junctions to adjoining VSMCs to induce vasorelaxation according to a mechanism known endothelial-dependent hyperpolarization (EDH).
Figure 5
Figure 5
The putative role of endothelial Ca2+ signaling in neurovascular coupling. Synaptic activity leads to arteriole and capillary vasodilation by inducing an increase in [Ca2+]i in postsynaptic neurons and perisynaptic astrocytes, as shown in Figure 2. Recent evidence indicated that synaptically-released glutamate may activate endothelial NMDARs, thereby eliciting the Ca2+-dependent activation of eNOS, in intraparenchymal arterioles. Moreover, acetylcholine may induce Ca2+-dependent NO release from brain endothelial cells by initiating the concerted interplay between InsP3Rs and SOCE [76]. This local vasodilation may be spread to more remote sites (≈ 500 μm) through the initiation of an interendothelial Ca2+ wave, which ignites NO release and PGI2 production as long as it travels along the endothelial monolayer. Moreover, this propagating Ca2+ sweep could induce vasodilation by also stimulating KCa channels and evoking EDH in arterioles. Finally, blood-borne autacoids and dietary agonists could induce vasodilation by, respectively, binding to their specific GPCRs and stimulating multiple TRP channels (TRPC3, TRPV3, TRPV4, TRPA1) to initiate EDH. Abbreviations: 20-HETE: 20-hydroxyeicosatetraenoic acid; AA: arachidonic acid; CX: cyclooxygenases 1 and 2; EETs: epoxyeicosatrienoic acids; GPCRs; G-protein-coupled receptors; InsP3: inositol-1,4,5-trisphosphate; KCa: Ca2+-activated intermediate and small conductance K+ channels; NO: nitric oxide; nNOS: neuronal NO synthase; P450: cytochrome P450; PGE2: prostaglandin E2; PL: phospholipase A2; PLD2: phospholipase D2; TRPs: TRP channels; VSMC: vascular smooth muscle cell.

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