Mechanisms underlying selective coupling of endothelial Ca2+signals with eNOSvs. IK/SK channels in systemic and pulmonary arteries
- 10 June 2020
- journal article
- research article
- Published by Wiley in The Journal of Physiology
- Vol. 598 (17), 3577-3596
- https://doi.org/10.1113/JP279570
Abstract
Key points Endothelial cell TRPV4 (TRPV4(EC)) channels exert a dilatory effect on the resting diameter of resistance mesenteric and pulmonary arteries. Functional intermediate- and small-conductance K+(IK and SK) channels and endothelial nitric oxide synthase (eNOS) are present in the endothelium of mesenteric and pulmonary arteries. TRPV4(EC)sparklets preferentially couple with IK/SK channels in mesenteric arteries and with eNOS in pulmonary arteries. TRPV4(EC)channels co-localize with IK/SK channels in mesenteric arteries but not in pulmonary arteries, which may explain TRPV4(EC)-IK/SK channel coupling in mesenteric arteries and its absence in pulmonary arteries. The presence of the nitric oxide-scavenging protein, haemoglobin alpha, limits TRPV4(EC)-eNOS signalling in mesenteric arteries. Spatial proximity of TRPV4(EC)channels with eNOS and the absence of haemoglobin alpha favour TRPV4(EC)-eNOS signalling in pulmonary arteries. Spatially localized Ca(2+)signals activate Ca2+-sensitive intermediate- and small-conductance K+(IK and SK) channels in some vascular beds and endothelial nitric oxide synthase (eNOS) in others. The present study aimed to uncover the signalling organization that determines selective Ca(2+)signal to vasodilatory target coupling in the endothelium. Resistance-sized mesenteric arteries (MAs) and pulmonary arteries (PAs) were used as prototypes for arteries with predominantly IK/SK channel- and eNOS-dependent vasodilatation, respectively. Ca(2+)influx signals through endothelial transient receptor potential vanilloid 4 (TRPV4(EC)) channels played an important role in controlling the baseline diameter of both MAs and PAs. TRPV4(EC)channel activity was similar in MAs and PAs. However, the TRPV4 channel agonist GSK1016790A (10 nm) selectively activated IK/SK channels in MAs and eNOS in PAs, revealing preferential TRPV4(EC)-IK/SK channel coupling in MAs and TRPV4(EC)-eNOS coupling in PAs. IK/SK channels co-localized with TRPV4(EC)channels at myoendothelial projections (MEPs) in MAs, although they lacked the spatial proximity necessary for their activation by TRPV4(EC)channels in PAs. Additionally, the presence of the NO scavenging protein haemoglobin alpha (Hb alpha) within nanometer proximity to eNOS limits TRPV4(EC)-eNOS signalling in MAs. By contrast, co-localization of TRPV4(EC)channels and eNOS at MEPs, and the absence of Hb alpha, favour TRPV4(EC)-eNOS coupling in PAs. Thus, our results reveal that differential spatial organization of signalling elements determines TRPV4(EC)-IK/SKvs. TRPV4(EC)-eNOS coupling in resistance arteries.Keywords
Funding Information
- National Institutes of Health (HL142808, HL146914, HL138496)
This publication has 69 references indexed in Scilit:
- UVB radiation generates sunburn pain and affects skin by activating epidermal TRPV4 ion channels and triggering endothelin-1 signalingProceedings of the National Academy of Sciences of the United States of America, 2013
- Endothelial cell expression of haemoglobin α regulates nitric oxide signallingNature, 2012
- Low intravascular pressure activates endothelial cell TRPV4 channels, local Ca 2+ events, and IK Ca channels, reducing arteriolar toneProceedings of the National Academy of Sciences of the United States of America, 2012
- Regulation of the human coronary microcirculationJournal of Molecular and Cellular Cardiology, 2012
- Endothelial Ca2+ wavelets and the induction of myoendothelial feedbackAmerican Journal of Physiology-Cell Physiology, 2012
- Sympathetic nerve stimulation induces local endothelial Ca2+ signals to oppose vasoconstriction of mouse mesenteric arteriesAmerican Journal of Physiology-Heart and Circulatory Physiology, 2012
- Calcium‐activated potassium channels and endothelial dysfunction: therapeutic options?British Journal of Pharmacology, 2009
- Functional architecture of inositol 1,4,5-trisphosphate signaling in restricted spaces of myoendothelial projectionsProceedings of the National Academy of Sciences of the United States of America, 2008
- Ca2+-activated K+ Channels in Murine Endothelial Cells: Block by Intracellular Calcium and MagnesiumThe Journal of general physiology, 2008
- Myoendothelial Gap Junctions May Provide the Pathway for EDHF in Mouse Mesenteric ArteryJournal of Vascular Research, 2003