Mechanisms underlying selective coupling of endothelial Ca2+ signals with eNOS vs. IK/SK channels in systemic and pulmonary arteries.

Spatially localized Ca2+ 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 Ca2+ 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. Ca2+ influx signals through endothelial transient receptor potential vanilloid 4 (TRPV4EC ) channels played an important role in controlling the baseline diameter of both MAs and PAs. TRPV4EC 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 TRPV4EC -IK/SK channel coupling in MAs and TRPV4EC -eNOS coupling in PAs. IK/SK channels co-localized with TRPV4EC channels at myoendothelial projections (MEPs) in MAs, although they lacked the spatial proximity necessary for their activation by TRPV4EC channels in PAs. Additionally, the presence of the NO scavenging protein haemoglobin α (Hbα) within nanometer proximity to eNOS limits TRPV4EC -eNOS signalling in MAs. By contrast, co-localization of TRPV4EC channels and eNOS at MEPs, and the absence of Hbα, favour TRPV4EC -eNOS coupling in PAs. Thus, our results reveal that differential spatial organization of signalling elements determines TRPV4EC -IK/SK vs. TRPV4EC -eNOS coupling in resistance arteries.