Precapillary sphincters and pericytes at first-order capillaries as key regulators for brain capillary perfusion

Abstract

Rises in local neural activity trigger local increases of cerebral blood flow, which is essential to match local energy demands. However, the specific location of microvascular flow control is incompletely understood. Here, we used two-photon microscopy to observe brain microvasculature in vivo. Small spatial movement of a three-dimensional (3D) vasculature makes it challenging to precisely measure vessel diameter at a single x–y plane. To overcome this problem, we carried out four-dimensional (x–y–z–t) imaging of brain microvessels during exposure to vasoactive molecules in order to constrain the impact of brain movements on the recordings. We demonstrate that rises in synaptic activity, acetylcholine, nitric oxide, cyclic guanosine monophosphate, ATP-sensitive potassium channels, and endothelin-1 exert far greater effects on brain precapillary sphincters and first-order capillaries than on penetrating arterioles or downstream capillaries, but with similar kinetics. The high level of responsiveness at precapillary sphincters and first-order capillaries was matched by a higher level of α-smooth muscle actin in pericytes as compared to penetrating arterioles and downstream capillaries. Mathematical modeling based on 3D vasculature reconstruction showed that precapillary sphincters predominantly regulate capillary blood flow and pressure as compared to penetrating arterioles and downstream capillaries. Our results confirm a key role for precapillary sphincters and pericytes on first-order capillaries as sensors and effectors of endothelium- or brain-derived vascular signals.

Gradual Not Sudden Change: Multiple Sites of Functional Transition Across the Microvascular Bed

“…injection or incubation of tissue with AlexaFluor 633 hydrazide ( Shen et al, 2012 ), but its role in microvascular regulation remains understudied. Recently, however, it has been used to identify intracortical arterioles in which endothelial caveolae were found to be critical players in neurovascular coupling ( Chow et al, 2020 ), and was found around precapillary sphincters branching off penetrating arterioles that regulate blood flow and pressure into the cortical capillary network ( Grubb et al, 2020 ; Zambach et al, 2021 ).…”

“…However, the same group found much more variable timings in neocortex of ketamine-medetomidine anaesthetized or awake mice, with capillaries or arterioles each being faster on some occasions ( Rungta et al, 2021 ), and in both these reports, mid-capillary dilations were very small (though these data conflate responders and non-responders, unlike some other studies, Hall et al, 2014 ; Shaw et al, 2021 ). Precapillary sphincters, where studied, have often shown larger dilations, as a proportion of their diameter, than adjacent arterioles and capillaries ( Grubb et al, 2020 ; Zambach et al, 2021 ).…”

Hypnotizability-Related Cerebral Blood Flow

“…Theoretically, the decrease in MCAv observed in med-highs during hyperventilation despite scarce changes in ABP, could be sustained by the sensitivity of their vessels muscle cells to blood pressure. The preferential effect of NO on precapillary sphincters and pericytes rather than on smooth muscle cells [67] may have contributed to the observed changes in MCAv. The lack of significant correlation between ΔMCAv and ΔPETCO2 occurring in both groups during rebreathing may be due to CO2 ceiling effect.…”

Metabolic Contribution and Cerebral Blood Flow Regulation by Astrocytes in the Neurovascular Unit

“…However, once again, it is at the capillary level that the astrocyte foot processes have the greatest influence [ 4 , 8 ]. The question of whether the capillaries themselves are responsible for the autonomous increase or decrease in the size of the vascular bed draws attention to the function of the pericytes that reside here [ 24 , 25 , 26 , 27 , 28 ]. It has long been reported that pericytes contain actin filaments, which have a contractile effect.…”

“…Regulation of the CBF is mainly mediated by vascular smooth muscle contraction and relaxation at the level of the upstream arterioles. However, it has been pointed out that pericytes may be involved in the dilatation and contraction of microvessels even at the capillary level [ 24 , 25 , 26 , 27 , 28 ]. In addition to pericyte regulation, the capillary bed size may also be actively regulated by an increase or decrease in water content in the Virchow–Robin space [ 29 , 30 , 31 ], the space between the astrocytic end feet and the outer surfaces of the microvessels.…”