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1 Anesthesiology, Baylor College of Medicine, Houston, Texas, United States; Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States; Medicine, Program of Cardiovascular Sciences, Baylor College of Medicine, Houston, Texas, United States
2 Dept. of Integrative Biology & Pharmacology, Univ. of Texas-Houston Health Sci Ctr, Houston, Texas, United States
3 Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas, United States
* To whom correspondence should be addressed. E-mail: marrelli{at}bcm.edu.
We previously demonstrated that 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. L-NAME and indomethacin were present throughout. In pressurized MCA, luminally delivered uridine triphosphate (UTP) produced increased EC intracellular calcium 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 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 endothelium by RT-PCR and immunofluorescence, respectively. Lastly, application of 4
-PDD, 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.
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