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Mechanisms underlying selective coupling of endothelial Ca 2+ signals with eNOS vs . IK/SK channels in systemic and pulmonary arteries
Author(s) -
Ottolini Matteo,
Daneva Zdravka,
Chen YenLin,
Cope Eric L.,
Kasetti Ramesh B.,
Zode Gulab S.,
Sonkusare Swapnil K.
Publication year - 2020
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp279570
Subject(s) - mesenteric arteries , enos , vasodilation , medicine , nitric oxide , endothelium , chemistry , cardiology , anatomy , nitric oxide synthase , endocrinology , artery
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 α, limits TRPV4 EC ‐eNOS signalling in mesenteric arteries. Spatial proximity of TRPV4 EC channels with eNOS and the absence of haemoglobin α favour TRPV4 EC ‐eNOS signalling in pulmonary arteries.Abstract Spatially localized Ca 2+ signals activate Ca 2+ ‐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 n m ) 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 α (Hbα) 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 Hbα, favour TRPV4 EC ‐eNOS coupling in PAs. Thus, our results reveal that differential spatial organization of signalling elements determines TRPV4 EC ‐IK/SK vs . TRPV4 EC ‐eNOS coupling in resistance arteries.