Functional Tuning of Intrinsic Endothelial Ca2+ Dynamics in Swine Coronary Arteries

• Published in: Circulation research Vol. 118; no. 7; pp. 1078 - 1090
• Main Authors: Francis, Michael, Waldrup, Joshua R, Qian, Xun, Solodushko, Viktoriya, Meriwether, John, Taylor, Mark S
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.04.2016
• Subjects: Animals; Calcium - metabolism; Calcium Channel Blockers - pharmacology; Calcium Signaling - drug effects; Calcium Signaling - physiology; Coronary Circulation - drug effects; Coronary Circulation - physiology; Coronary Vessels - metabolism; Endothelium, Vascular - metabolism; Female; Image Processing, Computer-Assisted; Inositol 1,4,5-Trisphosphate Receptors - drug effects; Inositol 1,4,5-Trisphosphate Receptors - physiology; Intermediate-Conductance Calcium-Activated Potassium Channels - physiology; Isometric Contraction; Male; Microscopy, Confocal; Models, Cardiovascular; Myography; Nitric Oxide Synthase Type III - physiology; Peptides; Potassium Channel Blockers - pharmacology; Small-Conductance Calcium-Activated Potassium Channels - physiology; Substance P - pharmacology; Sus scrofa; Swine; Tunica Intima - physiology; Vascular Resistance - drug effects; Vascular Resistance - physiology; coronary vessels; myography; substance P; potassium channels; calcium signaling
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.115.308141

RATIONALE:Recent data from mesenteric and cerebral beds have revealed spatially restricted Ca transients occurring along the vascular intima that control effector recruitment and vasodilation. Although Ca is pivotal for coronary artery endothelial function, spatial and temporal regulation of functional Ca signals in the coronary endothelium is poorly understood. OBJECTIVE:We aimed to determine whether a discrete spatial and temporal profile of Ca dynamics underlies endothelium-dependent relaxation of swine coronary arteries. METHODS AND RESULTS:Using confocal imaging, custom automated image analysis, and myography, we show that the swine coronary artery endothelium generates discrete basal Ca 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 but not by inhibition of ryanodine receptors or removal of extracellular Ca. In vessel rings, inhibition of specific Ca-dependent endothelial effectors, namely, small and intermediate conductance K channels (KCa3.1 and KCa2.3) and endothelial nitric oxide synthase, produces additive tone, which is blunted by internal store depletion or inositol 1,4,5-trisphosphate receptor blockade. Stimulation of endothelial inositol 1,4,5-trisphosphate–dependent signaling with substance P causes idiosyncratic changes in dynamic Ca signal parameters (active sites, event frequency, amplitude, duration, and spatial spread). Overall, substance P–induced vasorelaxation corresponded poorly with whole-field endothelial Ca measurements but corresponded precisely with the concentration-dependent change in Ca dynamics (linearly translated composite of dynamic parameters). CONCLUSIONS:Our findings show that endothelium-dependent control of swine coronary artery tone is determined by spatial and temporal titration of inherent endothelial Ca dynamics that are not represented by tissue-level averaged Ca changes.