The study of the mechanisms by which vasoactive molecules regulate pericyte contractility is in its infancy. Because ion channels are likely to be important in mediating the responses of pericytes to vasoactive signals, several laboratories have used electrophysiological methods to begin the task of determining the effect of these molecules on the ionic currents of pericytes. Also, because calcium regulates the contractile apparatus of pericytes, the effects of vaso-active molecules on the intracellular concentration of this divalent cation are of importance. However, at present, only a minority of the molecules known to alter pericyte contractility have been evaluated for effects on ion channel function and intracellular calcium levels.
Five molecules that induce retinal pericytes to contract have been analyzed for their effects on ion channel activity. These putative vasoactive signals include (1) acetylcholine, which activates muscarinic receptors to elicit pericyte contraction; (2) ATP acting via P2X7 and P2Y4 receptors; (3) endothelin-1, whose contractile effect is via ETA receptors; (4) platelet-derived growth factor-BB (PDGF-BB), which is the ligand for PGDF-b receptors; and (5) angiotensin II, for which the subclass of receptor mediating the contractile response of retinal pericytes remains to be determined.
For each of these putative vasoconstrictors, a depolarization of pericytes is caused by the opening of calcium-activated chloride channels (ClCa) and also, except for acetylcholine, the activation of calcium-permeable nonspecific cation (NSC) channels. In addition, an inhibition of ATP-sensitive potassium (KATP) channels, as has been demonstrated for endothelin-1, provides an additional mechanism by which vasoactive molecules can cause depolarization. With a decrease in the membrane potential, there is an opening of the L-type voltage-gated calcium channels (VGCCs), which are expressed by retinal pericytes (Figure 2).
Only two vasodilators have been tested for their effects on the ion channel activity of retinal pericytes. Adenosine, acting at A1 and A2a receptors, activates KATP channels. In contrast, nitric oxide (NO) does not affect KATP channels, but causes pericyte relaxation by a mechanism involving the cGMP-mediated inhibition of VGCCs.
There are two general mechanisms by which putative vasoconstrictors cause the intracellular concentration of calcium to increase in retinal pericytes (Figure 2). One is an influx of this divalent cation via calcium-permeable NSC channels and VGCCs. Another is the release of intracellular stores of calcium. These pathways for increasing cytoplas-mic calcium are interrelated. For example, the release of calcium stores is associated with the activation of the ClCa channels in retinal microvessels. In addition, it is likely that an influx of calcium triggers the release of stored calcium.
Both influx and release appear to contribute to the increase in pericyte calcium observed during exposure to the five tested vasoconstrictors, that is, acetylcholine, ATP, angiotensin II, endothelin-1, and platelet-derived growth factor BB. At present, the effects on pericyte calcium levels of the vasodilators adenosine and NO are not known. Future experimental study is needed to clarify the relative functional roles in pericytes of the NSC channels and the VGCCs. Also, the relative importance of calcium influx versus calcium release in regulating pericyte contractility is not well understood.
In the retinal microvasculature, pericytes are coupled by gap junctions to dozens of their neighboring vascular cells. Recently, Puro and colleagues discovered that molecules such as endothelin-1, angiotensin II, and extracellular ATP
potently and reversibly close these gap-junction pathways. Thus, vasoactive signals not only affect individual microvascular cells, but also regulate the effective size of the multicellular functional units that play a role in the control capillary blood flow. The regulation of intercellular communication within the pericyte-containing micro-vasculature may be an important, previously unappreciated mechanism by which local perfusion is dynamically affected by vasoactive molecules. Finally, the effects of putative vasoactive signals on the calcium sensitivity of the pericyte contractile apparatus remain to be determined.
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