Functional Tuning of Intrinsic Endothelial Ca2+ Dynamics in Swine Coronary Arteries
Rationale: Recent data from mesenteric and cerebral beds have revealed spatially restricted Ca2+ transients occurring along the vascular intima that control effector recruitment and vasodilation. While Ca2+ is pivotal for coronary artery endothelial function, spatial and temporal regulation of functional Ca2+ signals in the coronary endothelium is poorly understood.
Objective: We aimed to determine whether a discrete spatial and temporal profile of Ca2+ dynamics underlies endothelium-dependent relaxation of swine coronary arteries (SCA).
Methods and Results: Using confocal imaging, custom automated image analysis, and myography we show that the SCA endothelium generates discrete basal Ca2+ dynamics including isolated transients and whole-cell propagating waves. These events are suppressed by depletion of internal stores or inhibition of inositol 1,4,5-trisphosphate receptors (IP3R), but not by inhibition of ryanodine receptors or removal of extracellular Ca2+. In vessel rings, inhibition of specific Ca2+-dependent endothelial effectors, namely small and intermediate conductance K+channels (KCa3.1, KCa2.3) and endothelial nitric oxide synthase (eNOS), produces additive tone, which is blunted by internal store depletion or IP3R blockade. Stimulation of endothelial IP3-dependent signaling with substance P causes idiosyncratic changes in dynamic Ca2+ signal parameters (active sites, event frequency, amplitude, duration, and spatial spread). Overall, substance P-induced vasorelaxation corresponded poorly with whole-field endothelial Ca2+ measurements, but corresponded precisely with the concentration-dependent change in Ca2+ dynamics (linearly translated composite of dynamic parameters).
Conclusions: Our findings show that endothelium-dependent control of SCA tone is determined by spatial and temporal titration of inherent endothelial Ca2+ dynamics that are not represented by tissue-level averaged Ca2+ changes.
- KCa channels
- calcium signaling
- coronary artery
- endothelial function
- potassium channels
- endothelial nitric oxide synthase
- Received December 8, 2015.
- Revision received January 14, 2016.
- Accepted February 2, 2016.