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

Key Points: Endothelial cell TRPV4 (TRPV4 ) 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 sparklets preferentially couple with IK/SK channels in mesenteric arteries and with eNOS in pulmonary arteries. TRPV4 channels co-localize with IK/SK channels in mesenteric arteries but not in pulmonary arteries, which may explain TRPV4 -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 -eNOS signalling in mesenteric arteries. Spatial proximity of TRPV4 channels with eNOS and the absence of haemoglobin α favour TRPV4 -eNOS signalling in pulmonary arteries.

Abstract: Spatially localized Ca signals activate Ca -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 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 influx signals through endothelial transient receptor potential vanilloid 4 (TRPV4 ) channels played an important role in controlling the baseline diameter of both MAs and PAs. TRPV4 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 -IK/SK channel coupling in MAs and TRPV4 -eNOS coupling in PAs. IK/SK channels co-localized with TRPV4 channels at myoendothelial projections (MEPs) in MAs, although they lacked the spatial proximity necessary for their activation by TRPV4 channels in PAs. Additionally, the presence of the NO scavenging protein haemoglobin α (Hbα) within nanometer proximity to eNOS limits TRPV4 -eNOS signalling in MAs. By contrast, co-localization of TRPV4 channels and eNOS at MEPs, and the absence of Hbα, favour TRPV4 -eNOS coupling in PAs. Thus, our results reveal that differential spatial organization of signalling elements determines TRPV4 -IK/SK vs. TRPV4 -eNOS coupling in resistance arteries.