Abstract
Transient receptor potential vanilloid 4 (TRPV4) channel serves as a Ca2+ influx pathway in endothelial cells (ECs). The objective of this study was to identify elementary TRPV4 Ca2+ events in vascular ECs. We used third-order mesenteric arteries (MAs) from mice that express Ca2+ biosensor (GCaMP2) selectively in ECs. TRPV4 agonist GSK1016790A (GSK, 10 nM) produced EC-dependent dilation of pressurized MAs. High speed confocal imaging of slit-open MAs revealed that TRPV4 agonists (GSK, 4α-PDD, 11,12-EET) activate local Ca2+ events (“TRPV4 Ca2+ sparklets”) in ECs in absence of Ca2+ release from intracellular stores. Fractional fluorescence changes (ΔF/F0) for 19 event sites showed a quantal level of 0.22 ± 0.03. Mean open probability (NPs, N = number of quanta, Ps = probability of occurrence) of the sparklets at a site was 0.46 ± 0.06 (n = 10 sites), 0.19 ± 0.03 (n = 5 sites) and 0.57 ± 0.19 (n = 5 sites) for GSK (10 nM), 4α-PDD (5 μM) and 11, 12-EET (1 μM), respectively. TRPV4 inhibitor HC067047 (1 μM) significantly reduced NPs of GSK-induced sparklets to 0.16 ± 0.05 (n = 5 sites, p<0.05). In conclusion, this is the first detection of elementary TRPV4 Ca2+ sparklets that initiate EC-dependent vasodilation of resistance arteries. Supported by AHA-PHA 10POST3690006 (SKS) and NIH HL44455 (MTN).
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