Ion channels in capillary endothelium

Garcia, Daniela C.G.; Longden, Thomas A

doi:10.1016/bs.ctm.2020.01.005

Cited by 13 publications

(13 citation statements)

References 152 publications

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“…In addition to its hyperpolarization activation, it is sensitive to changes in cell volume and extracellular pH and is also activated by PKA (Nilius and Droogmans, 2003;Bi et al, 2014). As we have suggested previously for hyperpolarizing electrical signals generated in cECs, ClC-2 is an attractive candidate for mediating membrane repolarization (Garcia and Longden, 2020), in that its slow activation kinetics would enable K ir -mediated electrical signals to be generated and sent upstream before ClC-2 mediated Cl − current fully develops to repolarize the membrane. Accordingly, ClC-2 may fulfill a similar role in pericytes to initiate membrane repolarization in the wake of electrical signals generated by K ATP and K ir channels.…”

Section: Clc Channels May Repolarize the Membrane Following Electricamentioning

confidence: 83%

“…From this point, extensive ramification of the vascular bed greatly expands the surface area of the network, facilitating efficient exchange of nutrients and waste to rapidly satisfy the intense metabolic requirements of every neuron. The capillary bedconsisting of capillary ECs (cECs; Garcia and Longden, 2020) and overlying pericytes (see below) embedded in the basement membrane (a dense network of glycoproteins, collagens and secreted factors; Pozzi et al, 2017)-is incredibly dense, and each microliter of cortex holds approximately 1 m of blood vessels (Shih et al, 2015). Of these, around 90% by volume are capillaries (Gould et al, 2017).…”

Section: The Vascular Network Of the Brain Fundamental Angioarchitecturementioning

confidence: 99%

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The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

Hariharan

Weir

Robertson

et al. 2020

Front. Cell. Neurosci.

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Brain pericytes reside on the abluminal surface of capillaries, and their processes cover ~90% of the length of the capillary bed. These cells were first described almost 150 years ago (Eberth, 1871; Rouget, 1873) and have been the subject of intense experimental scrutiny in recent years, but their physiological roles remain uncertain and little is known of the complement of signaling elements that they employ to carry out their functions. In this review, we synthesize functional data with single-cell RNAseq screens to explore the ion channel and G protein-coupled receptor (GPCR) toolkit of mesh and thin-strand pericytes of the brain, with the aim of providing a framework for deeper explorations of the molecular mechanisms that govern pericyte physiology. We argue that their complement of channels and receptors ideally positions capillary pericytes to play a central role in adapting blood flow to meet the challenge of satisfying neuronal energy requirements from deep within the capillary bed, by enabling dynamic regulation of their membrane potential to influence the electrical output of the cell. In particular, we outline how genetic and functional evidence suggest an important role for Gs-coupled GPCRs and ATP-sensitive potassium (KATP) channels in this context. We put forth a predictive model for long-range hyperpolarizing electrical signaling from pericytes to upstream arterioles, and detail the TRP and Ca2+ channels and Gq, Gi/o, and G12/13 signaling processes that counterbalance this. We underscore critical questions that need to be addressed to further advance our understanding of the signaling topology of capillary pericytes, and how this contributes to their physiological roles and their dysfunction in disease.

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Section: Clc Channels May Repolarize the Membrane Following Electricamentioning

confidence: 83%

Section: The Vascular Network Of the Brain Fundamental Angioarchitecturementioning

confidence: 99%

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

Hariharan

Weir

Robertson

et al. 2020

Front. Cell. Neurosci.

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“…The membrane hyperpolarization provided by electrical signaling would increase Ca 2+ influx across the plasmalemma through cEC TRPV4 channels. Functional TRPA1 channels have also been reported in cECs ( 28 ), and Ca 2+ -permeable TRPC3, TRPM3, TRPP2, P2X4, P2X7, and Piezo1 channels have been detected at the mRNA level ( 29 ). Furthermore, IP 3 R-mediated Ca 2+ events lead to varying degrees of ER Ca 2+ depletion, which would cause activation of store-operated Ca 2+ entry (SOCE), the magnitude of which would be influenced by the driving force for Ca 2+ entry.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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“…The BBB and NVU are comprised of distinct cellular elements, viz., endothelial cells, pericytes and astrocytes, each of which plays important and specific roles in neurovascular function (Garcia and Longden, 2020;Mishra et al, 2016;Pandit et al, 2020;Villabona-Rueda et al, 2019). Among these cell types, astrocytes are unique in that they simultaneously contact neurons and the vasculature, thus enabling these cells to regulate blood flow in response to brain activity (Attwell et al, 2010;Belanger et al, 2011;Heithoff et al, 2021;Howarth, 2014).…”

Section: Graphical Abstract Introductionmentioning

confidence: 99%

“…The BBB and NVU are comprised of distinct cellular elements, viz., endothelial cells, pericytes and astrocytes, each of which plays important and specific roles in neurovascular function (Garcia and Longden, 2020;Mishra et al, 2016;Pandit et al, 2020;Villabona-Rueda et . CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”

Section: Graphical Abstract Introductionmentioning

confidence: 99%

Aging reduces calreticulin expression and alters spontaneous calcium signals in astrocytic endfeet of the mouse dorsolateral striatum

Zarate

Huntington

Bagher

et al. 2021

Preprint

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Aging-related impairment of the blood brain barrier (BBB) and neurovascular unit (NVU) increases risk for neurodegeneration. Among the various cells participating in BBB and NVU function, spontaneous Ca2+ signals in astrocytic endfeet are crucial for maintaining BBB and NVU integrity. To assess if aging is associated with changes in spontaneous Ca2+ signals within astrocytic endfeet of the dorsolateral striatum (DLS), we expressed a genetically encoded Ca2+ indicator, Lck-GCaMP6f in DLS astrocytes of young (3-4 month) and aging (20-24 month) mice. Compared to young mice, endfeet in the DLS of aging mice demonstrated a decrease in calreticulin (CALR) expression, and dramatic alterations in the dynamics of endfoot membrane-associated and mitochondrial Ca2+ signals. While young mice required both extracellular and endoplasmic reticulum (ER) Ca2+ sources for generating endfoot Ca2+ signals, aging mice showed exclusive dependence on ER Ca2+. These data suggest that aging is associated with significant changes in Ca2+ buffers and Ca2+ signals within astrocytic endfeet, which has important implications for understanding mechanisms involved in aging-related impairment of the BBB and NVU.

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Ion channels in capillary endothelium

Cited by 13 publications

References 152 publications

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

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

Aging reduces calreticulin expression and alters spontaneous calcium signals in astrocytic endfeet of the mouse dorsolateral striatum

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Ion channels in capillary endothelium

Cited by 13 publications

References 152 publications

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

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

Aging reduces calreticulin expression and alters spontaneous calcium signals in astrocytic endfeet of the mouse dorsolateral striatum

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