Abstract
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.
Highlights
A combination of autonomic signaling (Cipolla et al, 2004; Hamel, 2006) and intrinsic pressure sensing and metabolic autoregulatory mechanisms (Bayliss, 1902; Paulson et al, 1990) drives continual adjustments in global and local blood flow in the brain
Significant inroads toward a full understanding of these neurovascular coupling (NVC) mechanisms have been made in recent years (Iadecola, 2017), and in particular ion channel and G protein-coupled receptor (GPCR) signaling networks within and between the cells of the neurovascular unit [NVU; neurons, astrocytes, smooth muscle cells (SMCs), endothelial cells (ECs), and pericytes] are emerging as major contributors (Longden et al, 2016)
In the retina the inhibitory neurotransmitter and metabolic byproduct adenosine hyperpolarizes the rat retinal pericyte membrane potential by ∼30 mV through KATP channel engagement resulting from A1 and A2a adenosine receptor activation (Li and Puro, 2001), likely through engagement of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA)
Summary
A combination of autonomic signaling (Cipolla et al, 2004; Hamel, 2006) and intrinsic pressure sensing and metabolic autoregulatory mechanisms (Bayliss, 1902; Paulson et al, 1990) drives continual adjustments in global and local blood flow in the brain. There appear to be two major possible avenues through which vascular KATP channels could be engaged in pericytes: i) Changes in metabolism may couple KATP channel activity to membrane hyperpolarization.
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