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.
Supplemental Digital Content is Available in the Text.Reduced spinal cord blood flow leads to a hypoxia-mediated activation of hypoxia inducible factor 1α in dorsal horn neurons. This results in a carbonic anhydrase–dependent neuropathic pain.
Prostaglandin E2 (PGE2) has been widely proposed to mediate neurovascular coupling by dilating brain parenchymal arterioles through activation of prostanoid EP4 receptors. However, our previous report that direct application of PGE2 induces an EP1-mediated constriction strongly argues against its direct action on arterioles during neurovascular coupling, the mechanisms sustaining functional hyperemia. Recent advances have highlighted the role of capillaries in sensing neuronal activity and propagating vasodilatory signals to the upstream penetrating parenchymal arteriole. Here, we examined the effect of capillary stimulation with PGE2 on upstream arteriolar diameter using an ex vivo capillary-parenchymal arteriole preparation and in vivo cerebral blood flow measurements with two-photon laser-scanning microscopy. We found that PGE2 caused upstream arteriolar dilation when applied onto capillaries with an EC50 of 70 nM. The response was inhibited by EP1 receptor antagonist and was greatly reduced, but not abolished, by blocking the strong inward-rectifier K+ channel. We further observed a blunted dilatory response to capillary stimulation with PGE2 in a genetic mouse model of cerebral small vessel disease with impaired functional hyperemia. This evidence casts previous findings in a different light, indicating that capillaries are the locus of PGE2 action to induce upstream arteriolar dilation in the control of brain blood flow, thereby providing a paradigm-shifting view that nonetheless remains coherent with the broad contours of a substantial body of existing literature.
Relative to two-dimensional (2D) culture, three-dimensional (3D) culture of primary neurons has yielded increasingly physiological responses from cells. Electrospun nanofiber scaffolds are frequently used as a 3D biomaterial support for primary neurons in neural tissue engineering, while hydrophobic surfaces typically induce aggregation of cells. Poly-l-lactic acid (PLLA) was electrospun as aligned PLLA nanofiber scaffolds to generate a structure with both qualities. Primary cortical neurons from E18 Sprague–Dawley rats cultured on aligned PLLA nanofibers generated 3D clusters of cells that extended highly aligned, fasciculated neurite bundles within 10 days. These clusters were viable for 28 days and responsive to AMPA and GABA. Relative to the 2D culture, the 3D cultures exhibited a more developed profile; mass spectrometry demonstrated an upregulation of proteins involved in cortical lamination, polarization, and axon fasciculation and a downregulation of immature neuronal markers. The use of artificial neural network inference suggests that the increased formation of synapses may drive the increase in development that is observed for the 3D cell clusters. This research suggests that aligned PLLA nanofibers may be highly useful for generating advanced 3D cell cultures for high-throughput systems.
Neuronal computation is metabolically expensive and relies on the timely delivery of energy substrates via tightly controlled blood flow to prevent energetic deficits. The range of mechanisms responsible for this coupling of neural activity to blood flow are collectively termed ‘neurovascular coupling’ (NVC). These NVC mechanisms are typically assumed to be invariant and the possibility that they may be plastic, allowing reshaping of energy delivery according to ever-shifting neuronal metabolic needs, has not been considered. We present evidence that neuronal activity resculpts blood flow control mechanisms inherent to the endothelium, which forms the inner lining of all blood vessels, through a process we refer to as vascular signalling plasticity (VSP). Using an environmental enrichment paradigm, we find that housing mice in an environment that increases input to the barrel cortex drives profound synaptic plasticity within this network. This is accompanied by a remarkable resculpting of local vascular reactivity, augmenting the efficacy of mechanisms that signal for an increase in blood flow. This increase in sensitivity manifests as an increase red blood cell flux to capillary stimulation with extracellular K+, which activates strong inward rectifier K+ (Kir2.1) channel-dependent capillary-to-arteriole electrical signalling to elicit hyperemia. To support this augmentation, we find that VSP induces a ~70% increase in the density of Kir2.1 channels in endothelial cells membranes which is underlain by transcriptional and translational changes in capillary ECs. Using an ex vivo capillary-arteriole preparation, we demonstrate that this increase in membrane Kir2.1 channels translates into a profound shift in the sensitivity of capillaries to K+ stimulation to evoke upstream arteriolar dilation. Together, these results suggest that increasing neuronal energy consumption leads to a profound potentiation of the retrograde hyperpolarization generated by the endothelium during activity, enhancing upstream dilation at the penetrating arteriole and augmenting blood delivery to match enhanced local needs. Our data thus recast the capillary bed as a plastic, brain-wide, neural activity sensing network that is modulated at the molecular level by local neural input. This allows fine-tuning of existing blood delivery mechanisms to meet continually fluctuating neural energy needs. VSP represents a novel facet of brain plasticity that may be utilised by various physiological processes and may be disrupted in aging and in the broad range of brain pathologies that have a vascular component. Support for this work was provided by the NIH National Institute on Aging and National Institute of Neurological Disorders and Stroke (1R01AG066645, 5R01NS115401 [PI: S. Sakadžić], and 1DP2NS121347-01, to T.A.L), the American Heart Association (Awards 17SDG33670237 and 19IPLOI34660108 to T.A.L) and an NIH S10 grant (S10 OD026698, to University of Maryland School of Medicine CIBR Core Confocal Facility). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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