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lüll PLA2 and TRPV4 channels regulate endothelial calcium in cerebral arteries Marrelli SP; O'neil RG; Brown RC; Bryan RM JrAm J Physiol Heart Circ Physiol 2007[Mar]; 292 (3): H1390-7We previously demonstrated that endothelium-derived hyperpolarizing factor (EDHF)-mediated dilations in cerebral arteries are significantly reduced by inhibitors of PLA(2). In this study we examined possible mechanisms by which PLA(2) regulates endothelium-dependent dilation, specifically whether PLA(2) is involved in endothelial Ca(2+) regulation through stimulation of TRPV4 channels. Studies were carried out with middle cerebral arteries (MCA) or freshly isolated MCA endothelial cells (EC) of male Long-Evans rats. Nitro-l-arginine methyl ester (l-NAME) and indomethacin were present throughout. In pressurized MCA, luminally delivered UTP produced increased EC intracellular Ca(2+) concentration ([Ca(2+)](i)) and MCA dilation. Incubation with PACOCF(3), a PLA(2) inhibitor, significantly reduced both EC [Ca(2+)](i) and dilation responses to UTP. EC [Ca(2+)](i) was also partially reduced by a transient receptor potential vanilloid (TRPV) channel blocker, ruthenium red. Manganese quenching experiments demonstrated Ca(2+) influx across the luminal and abluminal face of the endothelium in response to UTP. Interestingly, PLA(2)-sensitive Ca(2+) influx occurred primarily across the abluminal face. Luminal application of arachidonic acid, the primary product of PLA(2) and a demonstrated activator of certain TRPV channels, increased both EC [Ca(2+)](i) and MCA diameter. TRPV4 mRNA and protein was demonstrated in the endothelium by RT-PCR and immunofluorescence, respectively. Finally, application of 4alpha-phorbol 12,13-didecanoate (4alphaPDD), a TRPV4 channel activator, produced an increase in EC [Ca(2+)](i) that was significantly reduced in the presence of ruthenium red. We conclude that PLA(2) is involved in EC Ca(2+) regulation through its regulation of TRPV4 channels. Furthermore, the PLA(2)-sensitive component of Ca(2+) influx may be polarized to the abluminal face of the endothelium.|Animals[MESH]|Arachidonic Acid/pharmacology[MESH]|Calcium/*physiology[MESH]|DNA Primers[MESH]|Endothelium, Vascular/drug effects/*physiology[MESH]|In Vitro Techniques[MESH]|Manganese/metabolism[MESH]|Middle Cerebral Artery/drug effects/*physiology[MESH]|Nitric Oxide Synthase Type III/genetics[MESH]|Phospholipases A/*metabolism[MESH]|Phospholipases A2[MESH]|Polymerase Chain Reaction[MESH]|Rats[MESH]|Ruthenium Red/pharmacology[MESH]|TRPV Cation Channels/*physiology[MESH] |