{"doi":"10.1073/pnas.2322135121","title":"WNK kinase is a vasoactive chloride sensor in endothelial cells","abstract":"Endothelial cells (ECs) line the wall of blood vessels and regulate arterial contractility to tune regional organ blood flow and systemic pressure. Chloride (Cl − ) is the most abundant anion in ECs and the Cl − sensitive With-No-Lysine (WNK) kinase is expressed in this cell type. Whether intracellular Cl − signaling and WNK kinase regulate EC function to alter arterial contractility is unclear. Here, we tested the hypothesis that intracellular Cl − signaling in ECs regulates arterial contractility and examined the signaling mechanisms involved, including the participation of WNK kinase. Our data obtained using two-photon microscopy and cell-specific inducible knockout mice indicated that acetylcholine, a prototypical vasodilator, stimulated a rapid reduction in intracellular Cl − concentration ([Cl − ] i ) due to the activation of TMEM16A, a Cl − channel, in ECs of resistance-size arteries. TMEM16A channel-mediated Cl − signaling activated WNK kinase, which phosphorylated its substrate proteins SPAK and OSR1 in ECs. OSR1 potentiated transient receptor potential vanilloid 4 (TRPV4) currents in a kinase-dependent manner and required a conserved binding motif located in the channel C terminus. Intracellular Ca 2+ signaling was measured in four dimensions in ECs using a high-speed lightsheet microscope. WNK kinase-dependent activation of TRPV4 channels increased local intracellular Ca 2+ signaling in ECs and produced vasodilation. In summary, we show that TMEM16A channel activation reduces [Cl − ] i , which activates WNK kinase in ECs. WNK kinase phosphorylates OSR1 which then stimulates TRPV4 channels to produce vasodilation. Thus, TMEM16A channels regulate intracellular Cl − signaling and WNK kinase activity in ECs to control arterial contractility.","journal":"Proceedings of the National Academy of Sciences","year":2024,"id":425945,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":428191,"name":"Briar Bell","orcid":"0000-0001-9797-6402","position":1,"is_corresponding":false},{"id":353065,"name":"Alejandro Mata‐Daboin","orcid":"0000-0003-1831-7842","position":2,"is_corresponding":false},{"id":1002191,"name":"Dieniffer Peixoto‐Neves","orcid":null,"position":3,"is_corresponding":false},{"id":827669,"name":"Daniel M. Collier","orcid":"0000-0001-9431-9271","position":4,"is_corresponding":false},{"id":298139,"name":"Julio F. Cordero-Morales","orcid":"0000-0002-6505-5403","position":5,"is_corresponding":false},{"id":353069,"name":"Jonathan H. Jaggar","orcid":"0000-0003-1505-3335","position":6,"is_corresponding":false},{"id":917739,"name":"Tessa A. C. Garrud","orcid":"0000-0002-7900-7939","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T01:58:32.160975Z","pmid":"38568964","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,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}