Local IP ₃ receptor–mediated Ca ²⁺ signals compound to direct blood flow in brain capillaries

Abstract

Healthy brain function depends on the finely tuned spatial and temporal delivery of blood-borne nutrients to active neurons via the vast, dense capillary network. Here, using in vivo imaging in anesthetized mice, we reveal that brain capillary endothelial cells control blood flow through a hierarchy of IP3 receptor–mediated Ca2+ events, ranging from small, subsecond protoevents, reflecting Ca2+ release through a small number of channels, to high-amplitude, sustained (up to ~1 min) compound events mediated by large clusters of channels. These frequent (~5000 events/s per microliter of cortex) Ca2+ signals are driven by neuronal activity, which engages Gq protein–coupled receptor signaling, and are enhanced by Ca2+ entry through TRPV4 channels. The resulting Ca2+-dependent synthesis of nitric oxide increases local blood flow selectively through affected capillary branches, providing a mechanism for high-resolution control of blood flow to small clusters of neurons.

Grey-box modeling and hypothesis testing of functional near-infrared spectroscopy-based cerebrovascular reactivity to anodal high-definition tDCS in healthy humans

“…Future investigation of *0.1 Hz oscillatory vessel response vis-à-vis neuronal response (EEG) to tDCS will develop a parameterized coupled oscillator (nonlinear) model for limit cycle behavior. The relation of the *0.1 Hz oscillatory vessel response vis-à-vis neuronal response may be related to the cortical excitability changes to anodal tDCS [132] due to the involvement of potassium and calcium dynamics [35,[133][134][135] in neurovascular communication that needs further investigation using tACS. Here, unlike tDCS, tACS can lead to physiological entrainment at the frequency of stimulation for system identification that can provide physiological insights based on a physiologically detailed model (see the Eqs 48-49 in the S1 Text).…”

Endothelial Ion Channels and Cell-Cell Communication in the Microcirculation

“…The terminal arteriole transitions and branches into 10–20 capillaries that form the capillary bed ( Figure 1 ). In the cerebral microcirculation, the initial capillary segment consists of an endothelial cell tube coated with contractile pericytes as shown in Figure 1 ( Gonzales et al, 2020 ; Longden et al, 2021 ; Thakore et al, 2021 ). Blood flow to the capillaries is controlled both by smooth muscle-induced changes in the diameter of the terminal arterioles ( Delashaw and Duling, 1988 ) and changes in the contractile activity of the pericytes in the initial segment ( Longden et al, 2017 , 2021 ; Thakore et al, 2021 ).…”

“…In the cerebral microcirculation, the initial capillary segment consists of an endothelial cell tube coated with contractile pericytes as shown in Figure 1 ( Gonzales et al, 2020 ; Longden et al, 2021 ; Thakore et al, 2021 ). Blood flow to the capillaries is controlled both by smooth muscle-induced changes in the diameter of the terminal arterioles ( Delashaw and Duling, 1988 ) and changes in the contractile activity of the pericytes in the initial segment ( Longden et al, 2017 , 2021 ; Thakore et al, 2021 ). Contractile pericytes located at branch points allow fine tuning of blood flow to capillaries adjacent to metabolically active parenchymal cells (neurons and glial cells in the case of the brain microcirculation; Gonzales et al, 2020 ; Longden et al, 2021 ).…”

“…Blood flow to the capillaries is controlled both by smooth muscle-induced changes in the diameter of the terminal arterioles ( Delashaw and Duling, 1988 ) and changes in the contractile activity of the pericytes in the initial segment ( Longden et al, 2017 , 2021 ; Thakore et al, 2021 ). Contractile pericytes located at branch points allow fine tuning of blood flow to capillaries adjacent to metabolically active parenchymal cells (neurons and glial cells in the case of the brain microcirculation; Gonzales et al, 2020 ; Longden et al, 2021 ). More distal portions of capillaries lose their coat of contractile pericytes and instead are associated with occasional pericytes that are non-contractile (not shown in Figure 1 ; Gonzales et al, 2020 ; Longden et al, 2021 ; Thakore et al, 2021 ).…”

“…Contractile pericytes located at branch points allow fine tuning of blood flow to capillaries adjacent to metabolically active parenchymal cells (neurons and glial cells in the case of the brain microcirculation; Gonzales et al, 2020 ; Longden et al, 2021 ). More distal portions of capillaries lose their coat of contractile pericytes and instead are associated with occasional pericytes that are non-contractile (not shown in Figure 1 ; Gonzales et al, 2020 ; Longden et al, 2021 ; Thakore et al, 2021 ). Capillaries then coalesce into venules that are invested with pericytic smooth muscle cells, rather than the circumferentially oriented arteriolar smooth muscle cells ( Jackson, 2012 ).…”