"A Step and a Ceiling": mechanical properties of Ca 2+ spark vasoregulation in resistance arteries by pressure-induced oxidative activation of PKG

• Published in: Physiological reports 2019-11, Vol.7 (22), p.e14260
• Main Authors: Csato, Viktoria, Kadir, Sharifah Z S A, Khavandi, Kaivan, Bennett, Hayley, Sugden, Sarah, Gurney, Alison M, Pritchard, Harry T, Hill-Eubanks, David, Eaton, Philip, Nelson, Mark T, Greenstein, Adam S
• Format: Article
• Language: English
• Subjects: Animals; Arteries; Caffeine; Calcium Signaling - drug effects; Calcium Signaling - physiology; Calcium signalling; Confocal microscopy; Cyclic GMP-Dependent Protein Kinases - metabolism; Enzyme Activation - drug effects; Enzyme Activation - physiology; Kinases; Male; Mechanical properties; Mesenteric Arteries - drug effects; Mesenteric Arteries - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Myography - methods; Organ Culture Techniques; Oxidants; Oxidants - pharmacology; Oxidation; Oxidative Stress - drug effects; Oxidative Stress - physiology; Physiology; Potassium channels; Pressure; Smooth muscle; Studies; Vasoconstriction - drug effects; Vasoconstriction - physiology; Veins & arteries
• ISSN: 2051-817X
• DOI: 10.14814/phy2.14260

We investigated the biomechanical relationship between intraluminal pressure within small mesenteric resistance arteries, oxidant activation of PKG, Ca sparks, and BK channel vasoregulation. Mesenteric resistance arteries from wild type (WT) and genetically modified mice with PKG resistance to oxidative activation were studied using wire and pressure myography. Ca sparks and Ca transients within vascular smooth muscle cells of intact arteries were characterized using high-speed confocal microscopy of intact arteries. Arteries were studied under conditions of varying intraluminal pressure and oxidation. Intraluminal pressure specifically, rather than the generic stretch of the artery, was necessary to activate the oxidative pathway. We demonstrated a graded step activation profile for the generation of Ca sparks and also a functional "ceiling" for this pressure --sensitive oxidative pathway. During steady state pressure - induced constriction, any additional Ca sensitive-K channel functional availability was independent of oxidant activated PKG. There was an increase in the amplitude, but not the Area under the Curve (AUC) of the caffeine-induced Ca transient in pressurized arteries from mice with oxidant-resistant PKG compared with wild type. Overall, we surmise that intraluminal pressure within resistance arteries controls Ca spark vasoregulation through a tightly controlled pathway with a graded onset switch. The pathway, underpinned by oxidant activation of PKG, cannot be further boosted by additional pressure or oxidation once active. We propose that these restrictive characteristics of pressure-induced Ca spark vasoregulation confer stability for the artery in order to provide a constant flow independent of additional pressure fluctuations or exogenous oxidants.