Ion channel networks in the control of cerebral blood flow

Abstract

One hundred and twenty five years ago, Roy and Sherrington made the seminal observation that neuronal stimulation evokes an increase in cerebral blood flow.(1) Since this discovery, researchers have attempted to uncover how the cells of the neurovascular unit-neurons, astrocytes, vascular smooth muscle cells, vascular endothelial cells and pericytes-coordinate their activity to control this phenomenon. Recent work has revealed that ionic fluxes through a diverse array of ion channel species allow the cells of the neurovascular unit to engage in multicellular signaling processes that dictate local hemodynamics.In this review we center our discussion on two major themes: (1) the roles of ion channels in the dynamic modulation of parenchymal arteriole smooth muscle membrane potential, which is central to the control of arteriolar diameter and therefore must be harnessed to permit changes in downstream cerebral blood flow, and (2) the striking similarities in the ion channel complements employed in astrocytic endfeet and endothelial cells, enabling dual control of smooth muscle from either side of the blood-brain barrier. We conclude with a discussion of the emerging roles of pericyte and capillary endothelial cell ion channels in neurovascular coupling, which will provide fertile ground for future breakthroughs in the field.

Keywords: Ion channels; astrocytic endfoot; calcium channels; calcium signaling; cerebral blood flow; cerebrovascular resistance; endothelium; functional hyperemia; neurovascular coupling; neurovascular unit; parenchymal arteriole; pial artery; potassium channels; smooth muscle; transient receptor potential channels.

Figure 1.

Anatomical features of the NVU and MEPs. (a) Electron micrograph depicting astrocytic endfeet (EF) enveloping a parenchymal arteriole with a single layer of SMCs and underlying ECs. Adjacent to the endfeet is the brain parenchyma (P) containing neuronal and astrocytic processes. Scale bar: 10 µm. (b) A MEP site through a fenestration in the internal elastic lamina (IEL) between an EC and SMC in a human parenchymal arteriole. Black arrowheads indicate a myoendothelial gap junction. Scale bar: 250 nm. Reproduced with permission from Aydin et al.

Figure 2.

Relationships between intravascular pressure, vessel diameter, [Ca²⁺]_i and V_m in pial arteries and parenchymal arterioles. (a) One fundamental difference between vessels of the cerebral circulation is that parenchymal arterioles develop more tone in response to lower intravascular pressure compared to pial arteries. (b) The phenomenon in A is linked to the parenchymal arteriole SM V_m, which is more depolarized in response to lower pressure compared to pial arteries. (c) Increases in [Ca²⁺]_i in response to increasing intravascular pressures are greater in parenchymal arterioles than in pial arteries owing to higher voltage-dependent calcium channel (VDCC) activity caused by the greater degree of SMC cell depolarization, as illustrated in (b). (d) There is no difference in the sensitivity of the SM contractile apparatus to Ca²⁺ between pial arteries and parenchymal arterioles, indicating that the difference in the pressure-constriction relationship between these two types of vessels is due to the difference in SM V_m in response to pressure. Data were re-plotted from ref. Parenchymal arteriole V_m data were obtained from F. Dabertrand (personal communication) and from Nystoriak et al. and Hannah et al.

Figure 3.

The central roles of SM TRPM4 channels and VDCCs in myogenic constriction of parenchymal arterioles. Intravascular pressure (∼40 mm Hg) activates G_q-coupled P2Y receptors on the SM, leading to PLC activation. Through an as-yet-undefined pathway in parenchymal arterioles (see text for insights from pial arteries), PLC activation leads to a depolarizing Na⁺ influx through TRPM4, triggering Ca²⁺ influx through VDCCs and leading to myocyte contraction.

Figure 4.

Feed-forward hyperpolarization of SMCs by K_IR channel activation by K⁺ and V_m. A small amount of K⁺ released from neurons or astrocytes during neuronal activity may activate K_IR channels on the SM and possibly also diffuse to K_IR channels on ECs. Activation of K_IR channels initiates membrane hyperpolarization, in the process promoting further K_IR channel activation to amplify hyperpolarization and lead to V_m reaching E_K. EC hyperpolarization, either due to K⁺ activation of K_IR or resulting from conducted signaling from downstream capillaries, could also be transmitted to the SMs by gap junctions, further amplifying SMC hyperpolarization.

Figure 5.

Schematic illustration of the central role of SM V_m in cerebrovascular constriction. Arrowheads indicate a stimulatory effect, whereas flat lines indicate a negative influence. TRP channel activity is engaged by pressure, which depolarizes the membrane and increases VDCC activity, leading to an increase in [Ca²⁺]_i and constriction. Membrane depolarization directly stimulates K_V channels, which mediate hyperpolarizing currents that, in turn, exert a negative feedback on depolarization; smooth muscle K_IR channel activation also counteracts depolarization. Under certain conditions, elevated [Ca²⁺]_i can induce RyR-mediated Ca²⁺ sparks, which couple to BK channels to hyperpolarize the membrane and limit depolarization. Astrocytic endfoot and endothelial signaling acts to hyperpolarize the SM membrane. The balance of these signaling elements controls Ca²⁺ entry into the myocyte and thus the contractile state of the cell. Adapted from Dabertrand et al.

Figure 6.

Neurovascular communication is initiated by neuronal activity, which drives the production of IP₃ by PLC, in turn initiating a propagating Ca²⁺ wave. Ca²⁺ waves arriving at the endfoot activate TRPV4 channels in a positive-feedback loop that further enhances their spread, ultimately leading to the stimulation of Ca²⁺-sensitive ion channels and enzymes.

Figure 7.

Astrocytic endfoot and EC K_Ca channel influences on SM V_m. Astrocytic Ca²⁺ waves initiated by neuronal activity can activate BK and IK channels directly on the endfoot. K⁺ accumulates in the restricted extracellular space, activating SM K_IR channels. Subsequent K⁺ efflux through these channels hyperpolarizes the SM membrane, which decreases VDCC open probability and thereby lowers global [Ca²⁺]_i to promote vasorelaxation. On the luminal side of the SM, the endothelium may be engaged during neurovascular coupling (for example by conducted signaling from the capillary bed or by luminal factors such as altered shear), leading to an increase in EC Ca²⁺ that could engage IK and/or SK channels in MEP microdomains to drive EC membrane hyperpolarization and also raise local K⁺. EC membrane hyperpolarization could then be transmitted via gap junctions to the overlying SM. EC and SM K_IR channels and Na⁺/K⁺ ATPase pumps could also respond to released K⁺ to amplify hyperpolarization.

Figure 8.

Neurovascular communication at the capillary level. Capillary ECs possess K_IR and TRPV4 channels, which can hyperpolarize the membrane and allow Ca²⁺ into the cytosol, respectively. K_IR channels may endow capillary ECs with the ability to sense K⁺ released by neuronal activity and to conduct a regenerative, retrograde hyperpolarization by virtue of the voltage-dependence of K_IR channels. This will lead to rapid upstream dilation of parenchymal arterioles and pial arteries. Pericytes cover more than one-third of the capillary surface area and express VDCCs as a major pathway for the delivery of Ca²⁺ for contraction. They also express K_ATP, K_Ca and K_IR channels, which could be recruited through various mechanisms triggered by neuronal activity to drive membrane hyperpolarization and induce pericyte relaxation. Collectively, ion channels in both ECs and pericytes may provide the means to finely control blood flow deep within the vascular tree.