{"doi":"10.1101/2025.08.17.670763","title":"Endothelial LRRC8C associates with LRRC8A and LRRC8B to regulate vascular reactivity and blood pressure","abstract":"Abstract Vascular tone is impacted by the endothelium’s ability to detect mechanical and chemical stimulation. L eucine- R ich R epeat- C ontaining protein 8 A, (LRRC8A), was previously identified as a required component of the mechanoresponsive endothelial LRRC8 complex regulating AKT-endothelial nitric oxide synthase (eNOS) signaling and vascular function. While LRRC8A is broadly expressed, LRRC8B, C, D and E have tissue-restricted expression. Here, we identified 2 single nucleotide polymorphisms (SNPs) in LRRC8C highly associated with elevated diastolic and systolic blood pressure in human genetic studies, implicating LRRC8C as a regulator of vascular function. While LRRC8A/B/C/D/E are expressed in endothelium, co-immunoprecipitation experiments from lung endothelium using Lrrc8a -3xFlag knock-in mice, Lrrc8c- HA knock-in mice and endothelium-specific Lrrc8a -3xFlag overexpression mice demonstrate the endothelial LRRC8 complex to be composed largely of LRRC8A/B/C heteromers. Lrrc8a/b/c knock-out studies in mice and knock-down studies in human umbilical vein endothelial cells show co-dependent expression of LRRC8A/B/C proteins, but not LRRC8D. Functionally, LRRC8A and LRRC8C depletion reduces endothelial volume regulatory anion channel (VRAC) currents, inhibits AKT-eNOS signaling, increases myogenic tone, impairs eNOS dependent vasodilation, and exacerbates angiotensin-induced hypertension. These data identify LRRC8A, LRRC8B and LRRC8C as components of the endothelial LRRC8 complex and reveal LRRC8C as having a non-redundant role in regulating endothelial AKT-eNOS, vascular relaxation and susceptibility to hypertension.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558807,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.958,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1354166,"name":"Yonghui Zhao","orcid":"0000-0002-4382-6334","position":1,"is_corresponding":false},{"id":1460037,"name":"Joshua Maurer","orcid":null,"position":2,"is_corresponding":false},{"id":708595,"name":"Prakash Arullampalam","orcid":"0000-0001-5725-2290","position":3,"is_corresponding":false},{"id":1460038,"name":"Nathaniel John","orcid":null,"position":4,"is_corresponding":false},{"id":1333945,"name":"John D. Tranter","orcid":"0009-0006-6884-7154","position":5,"is_corresponding":false},{"id":441567,"name":"Tarek Mohamed Abd El‐Aziz","orcid":"0000-0002-3441-9673","position":6,"is_corresponding":false},{"id":768433,"name":"Michelle Lin","orcid":"0000-0001-5367-1930","position":7,"is_corresponding":false},{"id":820202,"name":"Daniel J. Lerner","orcid":null,"position":8,"is_corresponding":false},{"id":395921,"name":"Carmen M. Halabi","orcid":"0000-0003-4889-8131","position":9,"is_corresponding":false},{"id":301602,"name":"Rajan Sah","orcid":"0000-0003-1092-1244","position":10,"is_corresponding":false},{"id":646331,"name":"Qiujun Yu","orcid":"0000-0003-0690-138X","position":0,"is_corresponding":true}],"reference_count":28,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:30.312295Z","pmid":"40894750","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":[]}