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PLA₂ and TRPV4 channels regulate endothelial calcium in cerebral arteries

Departments of ¹Anesthesiology, ²Molecular Physiology and Biophysics, and ³Graduate Program in Cardiovascular Sciences, Baylor College of Medicine, Houston; and ⁴Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas

Submitted 13 September 2006 ; accepted in final form 22 October 2006

We previously demonstrated that endothelium-derived hyperpolarizing factor (EDHF)-mediated dilations in cerebral arteries are significantly reduced by inhibitors of PLA₂. In this study we examined possible mechanisms by which PLA₂ regulates endothelium-dependent dilation, specifically whether PLA₂ is involved in endothelial Ca²⁺ 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 Ca²⁺ concentration ([Ca²⁺]_i) and MCA dilation. Incubation with PACOCF₃, a PLA₂ inhibitor, significantly reduced both EC [Ca²⁺]_i and dilation responses to UTP. EC [Ca²⁺]_i was also partially reduced by a transient receptor potential vanilloid (TRPV) channel blocker, ruthenium red. Manganese quenching experiments demonstrated Ca²⁺ influx across the luminal and abluminal face of the endothelium in response to UTP. Interestingly, PLA₂-sensitive Ca²⁺ influx occurred primarily across the abluminal face. Luminal application of arachidonic acid, the primary product of PLA₂ and a demonstrated activator of certain TRPV channels, increased both EC [Ca²⁺]_i and MCA diameter. TRPV4 mRNA and protein was demonstrated in the endothelium by RT-PCR and immunofluorescence, respectively. Finally, application of 4-phorbol 12,13-didecanoate (4PDD), a TRPV4 channel activator, produced an increase in EC [Ca²⁺]_i that was significantly reduced in the presence of ruthenium red. We conclude that PLA₂ is involved in EC Ca²⁺ regulation through its regulation of TRPV4 channels. Furthermore, the PLA₂-sensitive component of Ca²⁺ influx may be polarized to the abluminal face of the endothelium.

fura 2; manganese quenching; transient receptor potential; endothelium-derived hyperpolarizing factor; phospholipase A₂; brain

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