Roles of endothelial prostaglandin I in maintaining synchronous spontaneous Ca transients in rectal capillary pericytes.

In hollow visceral organs, capillary pericytes appear to drive spontaneous Ca transients in the upstream arterioles. Here, mechanisms underlying the intercellular synchrony of pericyte Ca transients were explored. Ca dynamics in NG2 chondroitin sulphate proteoglycan (NG2)-expressing capillary pericytes were examined using rectal mucosa-submucosa preparations of NG2-GCaMP6 mice. Spontaneous Ca transients arising from endoplasmic reticulum Ca release were synchronously developed amongst capillary pericytes in a gap junction blocker (3 μM carbenoxolone)-sensitive manner and could spread into upstream vascular segments. Spontaneous Ca transients were suppressed by the Ca -activated Cl channel (CaCC) blocker niflumic acid and their synchrony was diminished by a TMEM16A inhibitor (3 μM Ani9) in accordance with TMEM16A immunoreactivity in pericytes. In capillaries where cyclooxygenase (COX)-2 immunoreactivity was expressed in endothelium but not pericytes, non-selective COX inhibitors (1 μM indomethacin or 10 μM diclofenac) or COX-2 inhibitor (10 μM NS 398) disrupted the synchrony of spontaneous Ca transients and raised the basal Ca level. Subsequent prostaglandin I (PGI ; 100 nM) or the K channel opener levcromakalim restored the synchrony with a reduction in the Ca level. PGI receptor antagonist (1 μM RO1138452) also disrupted the synchrony of spontaneous Ca transients and increased the basal Ca level. Subsequent levcromakalim restored the synchrony and reversed the Ca rise. Thus, the synchrony of spontaneous Ca transients in pericytes appears to be developed by the spread of spontaneous transient depolarisations arising from the opening of TMEM16A CaCCs. Endothelial PGI may play a role in maintaining the synchrony, presumably by stabilising the resting membrane potential in pericytes. KEY POINTS: Capillary pericytes in the rectal mucosa generate synchronous spontaneous Ca transients that could spread into the upstream vascular segment. Spontaneous Ca release from the endoplasmic reticulum (ER) triggers the opening of Ca -activated Cl channel TMEM16A and resultant depolarisations that spread amongst pericytes via gap junctions, establishing the synchrony of spontaneous Ca transients in pericytes. Prostaglandin I (PGI ), which is constitutively produced by the endothelium depending on cyclooxygenase-2, appears to prevent premature ER Ca releases in the pericytes allowing periodic, regenerative Ca releases. Endothelial PGI may maintain the synchrony of pericyte activity by stabilising pericyte resting membrane potential by opening of K channels.