{"doi":"10.1152/ajpheart.01006.2006","title":"PLA<sub>2</sub> and TRPV4 channels regulate endothelial calcium in cerebral arteries","abstract":"<jats:p> We previously demonstrated that endothelium-derived hyperpolarizing factor (EDHF)-mediated dilations in cerebral arteries are significantly reduced by inhibitors of PLA<jats:sub>2</jats:sub>. In this study we examined possible mechanisms by which PLA<jats:sub>2</jats:sub> regulates endothelium-dependent dilation, specifically whether PLA<jats:sub>2</jats:sub> is involved in endothelial Ca<jats:sup>2+</jats:sup> 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<jats:sup>2+</jats:sup> concentration ([Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>) and MCA dilation. Incubation with PACOCF<jats:sub>3</jats:sub>, a PLA<jats:sub>2</jats:sub> inhibitor, significantly reduced both EC [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> and dilation responses to UTP. EC [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> was also partially reduced by a transient receptor potential vanilloid (TRPV) channel blocker, ruthenium red. Manganese quenching experiments demonstrated Ca<jats:sup>2+</jats:sup> influx across the luminal and abluminal face of the endothelium in response to UTP. Interestingly, PLA<jats:sub>2</jats:sub>-sensitive Ca<jats:sup>2+</jats:sup> influx occurred primarily across the abluminal face. Luminal application of arachidonic acid, the primary product of PLA<jats:sub>2</jats:sub> and a demonstrated activator of certain TRPV channels, increased both EC [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> and MCA diameter. TRPV4 mRNA and protein was demonstrated in the endothelium by RT-PCR and immunofluorescence, respectively. Finally, application of 4α-phorbol 12,13-didecanoate (4αPDD), a TRPV4 channel activator, produced an increase in EC [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> that was significantly reduced in the presence of ruthenium red. We conclude that PLA<jats:sub>2</jats:sub> is involved in EC Ca<jats:sup>2+</jats:sup> regulation through its regulation of TRPV4 channels. Furthermore, the PLA<jats:sub>2</jats:sub>-sensitive component of Ca<jats:sup>2+</jats:sup> influx may be polarized to the abluminal face of the endothelium. </jats:p>","journal":"American Journal of Physiology-Heart and Circulatory Physiology","year":2007,"id":28182,"datarank":5.790321939568539,"base_score":4.859812404361672,"endowment":4.859812404361672,"self_citation_contribution":0.7289718606542509,"citation_network_contribution":5.0613500789142885,"self_endowment_contribution":0.7289718606542509,"citer_contribution":5.0613500789142885,"corpus_percentile":null,"corpus_rank":null,"citation_count":128,"citer_count":122,"citers_with_citation_signal":117,"citers_with_endowment":117,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":158526,"name":"Roger G. 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Marrelli","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":4.859812404361672,"endowment":4.859812404361672,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"17071727","pmcid":null,"openalex_id":"https://openalex.org/W2027375644","authors":[],"funders":[{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS-46666","title":null}],"total_grants":1,"fwci":4.3034,"citation_percentile":0.94566064,"influential_citations":6,"citation_trend":[{"year":2012,"count":8},{"year":2013,"count":11},{"year":2014,"count":9},{"year":2015,"count":5},{"year":2016,"count":9},{"year":2017,"count":2},{"year":2018,"count":5},{"year":2019,"count":7},{"year":2020,"count":9},{"year":2021,"count":12},{"year":2022,"count":2},{"year":2023,"count":7},{"year":2024,"count":4},{"year":2026,"count":1}],"oa_status":"closed","license":null,"oa_locations":[{"url":"https://www.physiology.org/doi/pdf/10.1152/ajpheart.01006.2006","host_type":"publisher"},{"url":"https://doi.org/10.1152/ajpheart.01006.2006","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/17071727","host_type":"repository"}],"fields_of_study":["Vanadium and Halogenation Chemistry","Ion Channels and Receptors","Cardiovascular, Neuropeptides, and Oxidative Stress Research","Chemistry","Medicine","Animals","Arachidonic Acid","Calcium","DNA Primers","Endothelium, Vascular","In Vitro Techniques","Manganese","Middle Cerebral Artery","Nitric Oxide Synthase Type III","Phospholipases A","Phospholipases A2","Polymerase Chain Reaction","Rats","Ruthenium Red","TRPV Cation Channels"],"mesh_terms":["Animals","Calcium","Endothelium, Vascular","Manganese","Phospholipases A","Ruthenium Red","Polymerase Chain Reaction","Arachidonic Acid","DNA Primers","Middle Cerebral Artery","TRPV Cation Channels","Rats","Nitric Oxide Synthase Type III","Phospholipases A2","In Vitro Techniques"],"keywords":["TRPV4","TRPV","Ruthenium red","Cerebral arteries","Endothelium","Transient receptor potential channel","Chemistry","Endocrinology","Lysophosphatidic acid","Calcium","Voltage-dependent calcium channel","Internal medicine","Biochemistry","Biology","Receptor","Medicine","TRPV1"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-08T20:48:29.683313Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}