Brain capillary pericytes are metabolic sentinels that control blood flow through a KATP channel-dependent energy switch

Hariharan, Ashwini; Robertson, Colin D.; Garcia, Daniela C.G.; Longden, Thomas A

doi:10.1016/j.celrep.2022.111872

Cited by 35 publications

(36 citation statements)

References 107 publications

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“…2c–g and Tables S1 and S2 ). To further test the effect of membrane voltage on mid-capillary pericyte Ca 2+ , we pharmacologically altered K ATP channel activity, whose modulation has been shown to have large effects on pericyte membrane potential 37 – 39 . Consistent with our above results showing that mid-capillary Ca 2+ transients were independent of VGCCs, application of pinacidil (10 µM), a K ATP channel opener which hyperpolarizes pericytes, had no effect on transient frequency in processes or the soma (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Although our data suggests Ca 2+ influx in mid-capillary pericytes occurs primarily via non-voltage-gated channels, this does not exclude a role for pericyte hyperpolarization in functional hyperemia. Several reports on pericyte membrane potential have been made in various preparations from different regions of the CNS, reporting mean resting membrane potentials of between −35 mV and −50 mV 10 , 28 , 37 – 39 , 50 . In pressurized intact retina preparations, pericytes across the vascular arbor are found more depolarized than smooth muscle cells at low pressure (−43 mV vs. −64 mV) 50 , suggesting pericytes have lower K + permeability at rest.…”

Section: Discussionmentioning

confidence: 99%

“…In pressurized intact retina preparations, pericytes across the vascular arbor are found more depolarized than smooth muscle cells at low pressure (−43 mV vs. −64 mV) 50 , suggesting pericytes have lower K + permeability at rest. Opening of K ATP channels increases K + permeability of mid-capillary pericytes, and therefore causes a robust hyperpolarization 37 – 39 , which can then be propagated to upstream mural and endothelial cells 37 , 39 . Retrograde hyperpolarization is a robust phenomenon in the microvasculature which rapidly closes VGCCs on upstream SMCs and ensheathing pericytes, thereby decreasing intracellular Ca 2+ and dilating these contractile cells to increase local cerebral blood flow 9 , 27 , 53 – 55 .…”

Section: Discussionmentioning

confidence: 99%

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Orai, RyR, and IP3R channels cooperatively regulate calcium signaling in brain mid-capillary pericytes

et al. 2023

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Pericytes are multifunctional cells of the vasculature that are vital to brain homeostasis, yet many of their fundamental physiological properties, such as Ca2+ signaling pathways, remain unexplored. We performed pharmacological and ion substitution experiments to investigate the mechanisms underlying pericyte Ca2+ signaling in acute cortical brain slices of PDGFRβ-Cre::GCaMP6f mice. We report that mid-capillary pericyte Ca2+ signalling differs from ensheathing type pericytes in that it is largely independent of L- and T-type voltage-gated calcium channels. Instead, Ca2+ signals in mid-capillary pericytes were inhibited by multiple Orai channel blockers, which also inhibited Ca2+ entry triggered by endoplasmic reticulum (ER) store depletion. An investigation into store release pathways indicated that Ca2+ transients in mid-capillary pericytes occur through a combination of IP3R and RyR activation, and that Orai store-operated calcium entry (SOCE) is required to sustain and amplify intracellular Ca2+ increases evoked by the GqGPCR agonist endothelin-1. These results suggest that Ca2+ influx via Orai channels reciprocally regulates IP3R and RyR release pathways in the ER, which together generate spontaneous Ca2+ transients and amplify Gq-coupled Ca2+ elevations in mid-capillary pericytes. Thus, SOCE is a major regulator of pericyte Ca2+ and a target for manipulating their function in health and disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Orai, RyR, and IP3R channels cooperatively regulate calcium signaling in brain mid-capillary pericytes

et al. 2023

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“…In rodent (particularly murine) studies, genetically engineered animals can express reporter proteins to signal the location and physiological reaction parameters of pericytes for experimental purposes. 7,[17][18][19][20][21] However, these methods are not applicable to human brain research. There are likely differences between human and rodent species in physiology-the human brain is very different from that of mice, as the species diverged evolutionarily $75-95 million years ago.…”

Section: Introductionmentioning

confidence: 99%

“…astrocytes and endothelial cells). [1][2][3][4][5][6][7][8][9] Pericyte dysfunction is now recognised as a potential contributor to the progression of vascular diseases and neurodegenerative diseases, particularly in persons of advanced age. 5,[10][11][12][13][14][15][16] Despite the burgeoning scientific literature on pericyte biology, much remains to be learned about this fascinating cell type.…”

Section: Introductionmentioning

confidence: 99%

A high‐throughput single‐cell RNA expression profiling method identifies human pericyte markers

Sziraki,

Zhong,

Neltner

et al. 2023

Neuropathology Appl Neurobio

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AimsWe sought to identify and optimize a universally available histological marker for pericytes in the human brain. Such a marker could be a useful tool for researchers. Further, identifying a gene expressed relatively specifically in human pericytes could provide new insights into the biological functions of this fascinating cell type.MethodsWe analysed single‐cell RNA expression profiles derived from different human and mouse brain regions using a high‐throughput and low‐cost single‐cell transcriptome sequencing method called EasySci. Throughthis analysis, we were able to identify specific gene markers for pericytes, some of which had not been previously characterized. We then used commercially (and therefore universally) available antibodies to immunolabel the pericyte‐specific gene products in formalin‐fixed paraffin‐embedded (FFPE) human brains, and also performed immunoblots to determine whether appropriately sized proteins were recognized.ResultsIn the EasySci data sets, highly pericyte‐enriched expression was notable for SLC6A12 and SLC19A1. Antibodies against these proteins recognized bands of the correct size in immunoblots of human brain extracts. Following optimization of the immunohistochemical technique, staining for both antibodies was strongly positive in small blood vessels, and was far more effective than a PDGFRB antibody at staining pericyte‐like cells in FFPE human brain sections. In an exploratory sample of other human organs (kidney, lung, liver, muscle), immunohistochemistry did not show the same pericyte‐like pattern of staining.ConclusionsThe SLC6A12 antibody was well suited for labelling pericytes in human FFPE brain sections, based on the combined results of single‐cell RNA‐seq analyses, immunoblots, and immunohistochemical studies.

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Brain microvascular endothelial cell metabolism and its ties to barrier function

Weber,

Moiz,

Clyne

2024

Blood-Brain Barrier

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Brain capillary pericytes are metabolic sentinels that control blood flow through a KATP channel-dependent energy switch

Cited by 35 publications

References 107 publications

Orai, RyR, and IP3R channels cooperatively regulate calcium signaling in brain mid-capillary pericytes

Orai, RyR, and IP3R channels cooperatively regulate calcium signaling in brain mid-capillary pericytes

A high‐throughput single‐cell RNA expression profiling method identifies human pericyte markers

Brain microvascular endothelial cell metabolism and its ties to barrier function

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