Electrotonic Transmission Within Pericyte-Containing Retinal Microvessels
ABSTRACT Little is known about the electrotonic architecture of the pericyte-containing retinal microvasculature. Here, the authors focus on the cell-to-cell transmission of hyperpolarization, which can induce abluminal pericytes to relax and lumens to dilate.
With perforated-patch pipettes, the authors monitored the membrane potentials and ionic currents of pairs of pericytes located on freshly isolated rat retinal microvessels. Voltage changes were induced by administering electrical stimuli into pericytes, miniperfusing the KATP channel opener pinacidil, or using oxotremorine to activate chloride channels.
Suggestive of extensive cell-to-cell communication, spontaneous voltage changes were strikingly similar in widely separated pericytes. In addition, injection of current into one of a pair of sampled pericytes always elicited a voltage response in the other sampled pericyte; the gap junction uncoupler, heptanol, blocked this transmission. In the dual recordings, hyperpolarization spreading from a current-injected pericyte decayed approximately 40% within 100 microm. In contrast, pinacidil-induced hyperpolarizations diminished by only approximately 2% in 100 microm. Depolarizations also appeared to spread with similar transmission efficacies.
Based on the experiments, the authors propose that key features of the electrotonic architecture of retinal microvessels include highly efficient cell-to-cell communication within the endothelium and relatively inefficient transmission at pericyte/endothelial junctions. Thus, the endothelium is likely to provide an efficient pathway that functionally links contractile pericytes and thereby, serves to coordinate the vasomotor response of a retinal capillary.
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- "Our knowledge of the Ca 2+ signals in the individual cell types of the intact microcirculation is rudimentary. This is especially the case for pericytes, the cells that have recently been shown to affect diameter in capillaries            and venules    . Pericytes have been described differently depending upon where they have been isolated from, but there has been no systematic study of identified cells in the intact microcirculation, and thus we do not know if contraction and Ca 2+ rises are a universal or a restricted function of pericytes populations [16,20,22,31–36]. "
ABSTRACT: The microcirculation is the site of gas and nutrient exchange. Control of central or local signals acting on the myocytes, pericytes and endothelial cells within it, is essential for health. Due to technical problems of accessibility, the mechanisms controlling Ca(2+) signalling and contractility of myocytes and pericytes in different sections of microvascular networks in situ have not been investigated. We aimed to investigate Ca(2+) signalling and functional responses, in a microcirculatory network in situ. Using live confocal imaging of ureteric microvascular networks, we have studied the architecture, morphology, Ca(2+) signalling and contractility of myocytes and pericytes. Ca(2+) signals vary between distributing arcade and downstream transverse and precapillary arterioles, are modified by agonists, with sympathetic agonists being ineffective beyond transverse arterioles. In myocytes and pericytes, Ca(2+) signals arise from Ca(2+) release from the sarcoplasmic reticulum through inositol 1,4,5-trisphosphate-induced Ca(2+) release and not via ryanodine receptors or Ca(2+) entry into the cell. The responses in pericytes are less oscillatory, slower and longer-lasting than those in myocytes. Myocytes and pericytes are electrically coupled, transmitting Ca(2+) signals between arteriolar and venular networks dependent on gap junctions and Ca(2+) entry via L-type Ca(2+) channels. Endothelial Ca(2+) signalling inhibits intracellular Ca(2+) oscillations in myocytes and pericytes via L-arginine/nitric oxide pathway and intercellular propagating Ca(2+) signals via EDHF. Increases of Ca(2+) in pericytes and myocytes constrict all vessels except capillaries. These data reveal the structural and signalling specializations allowing blood flow to be regulated by myocytes and pericytes.Cell calcium 07/2013; 54(3). DOI:10.1016/j.ceca.2013.06.001 · 4.21 Impact Factor
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- "Notably, in spite of a lack of dye coupling between neighboring pericytes, the constriction observed in response to the electrical stimulation of one cell, was also observed at distant pericyte-controlled regions after a few tens of seconds (Peppiatt et al., 2006). This interesting result suggests that pericytes either release their own diffusible factors which travel appreciable distances to affect adjacent pericytes, or pericytes are communicating to each other by utilizing other cell types, which may include the endothelial cells of the capillary to which pericytes are physically connected via gap junctions (Wu et al., 2006) or the surrounding astrocyte syncytium. The latter possibility may explain why pericytes are sensitive to ATP, which is a ubiquitous astrocyte transmitter utilized for long-range paracrine signaling (Guthrie et al., 1999). "
ABSTRACT: The control of cerebral vessel diameter is of fundamental importance in maintaining healthy brain function because it is critical to match cerebral blood flow (CBF) to the metabolic demand of active neurons. Recent studies have shown that astrocytes are critical players in the regulation of cerebral blood vessel diameter and that there are several molecular pathways through which astrocytes can elicit these changes. Increased intracellular Ca(2+) in astrocytes has demonstrated a dichotomy in vasomotor responses by causing the constriction as well as the dilation of neighboring blood vessels. The production of arachidonic acid (AA) in astrocytes by Ca(2+) sensitive phospholipase A(2) (PLA(2)) has been shown to be common to both constriction and dilation mechanisms. Constriction results from the conversion of AA to 20-hydroxyeicosatetraenoic acid (20-HETE) and dilation from the production of prostaglandin E(2) (PGE2) or epoxyeicosatrienoic acid (EET) and the level of nitric oxide (NO) appears to dictate which of these two pathways is recruited. In addition the activation of Ca(2+) activated K(+) channels in astrocyte endfeet and the efflux of K(+) has also been suggested to modify vascular tone by hyperpolarization and relaxation of smooth muscle cells (SMCs). The wide range of putative pathways indicates that more work is needed to clarify the contributions of astrocytes to vascular dynamics under different cellular conditions. Nonetheless it is clear that astrocytes are important albeit complicated regulators of CBF.Glia 09/2007; 55(12):1214-21. DOI:10.1002/glia.20543 · 6.03 Impact Factor
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ABSTRACT: Although inwardly rectifying potassium (K(IR)) channels are known to have important functional roles in arteries and arterioles, knowledge of these channels in pericyte-containing microvessels is limited. A working hypothesis is that K(IR) channel activity affects the membrane potential and thereby the contractile tone of abluminal pericytes whose contractions and relaxations may regulate capillary perfusion. Because pericyte function is thought to be particularly important in the retina, we used the perforated-patch technique to monitor the ionic currents of pericytes located on microvessels freshly isolated from the rat retina. In addition, because changes in ion channel function may contribute to microvascular dysfunction in the diabetic retina, we also recorded from pericyte-containing microvessels of streptozotocin-injected rats. Using barium to identify K(IR) currents, we found that there is a topographical heterogeneity of these currents in the pericyte-containing microvasculature of the normal retina. Specifically, the K(IR) current detected at distal locations is strongly rectifying, but the proximal K(IR) current is weakly rectifying and has a smaller inward conductance. However, soon after the onset of diabetes, these differences diminish as the rectification and inward conductance of the proximal K(IR) current increase. These diabetes-induced changes were reversed by an inhibitor of polyamine synthesis and could be mimicked by spermine, whose concentration is elevated in the diabetic eye. Hence, spermine is a candidate for mediating the effect of diabetes on the function of microvascular K(IR) channels. In addition, our findings raise the possibility that functional changes in K(IR) channels contribute to blood flow dysregulation in the diabetic retina.The Journal of Physiology 07/2006; 573(Pt 2):483-95. DOI:10.1113/jphysiol.2006.107102 · 4.54 Impact Factor