{"doi":"10.1093/function/zqac017","title":"Endothelial Cullin3 Mutation Impairs Nitric Oxide-Mediated Vasodilation and Promotes Salt-Induced Hypertension","abstract":"Abstract Human hypertension caused by in-frame deletion of CULLIN3 exon-9 (Cul3∆9) is driven by renal and vascular mechanisms. We bred conditionally activatable Cul3∆9 transgenic mice with tamoxifen-inducible Tie2-CREERT2 mice to test the importance of endothelial Cul3. The resultant mice (E-Cul3∆9) trended towards elevated nighttime blood pressure (BP) correlated with increased nighttime activity, but displayed no difference in daytime BP or activity. Male and female E-Cul3∆9 mice together exhibited a decline in endothelial-dependent relaxation in carotid artery. Male but not female E-Cul3∆9 mice displayed severe endothelial dysfunction in cerebral basilar artery. There was no impairment in mesenteric artery and no difference in smooth muscle function, suggesting the effects of Cul3∆9 are arterial bed-specific and sex-dependent. Expression of Cul3∆9 in primary mouse aortic endothelial cells decreased endogenous Cul3 protein, phosphorylated (S1177) endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production. Protein phosphatase (PP) 2A, a known Cul3 substrate, dephosphorylates eNOS. Cul3∆9-induced impairment of eNOS activity was rescued by a selective PP2A inhibitor okadaic acid, but not by a PP1 inhibitor tautomycetin. Because NO deficiency contributes to salt-induced hypertension, we tested the salt-sensitivity of E-Cul3∆9 mice. While both male and female E-Cul3∆9 mice developed salt-induced hypertension and renal injury, the pressor effect of salt was greater in female mutants. The increased salt-sensitivity in female E-Cul3∆9 mice was associated with decreased renovascular relaxation and impaired natriuresis in response to a sodium load. Thus, CUL3 mutations in the endothelium may contribute to human hypertension in part through decreased endothelial NO bioavailability, renovascular dysfunction, and increased salt-sensitivity of BP.","journal":"Function","year":2022,"id":257435,"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":0.9513,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":490953,"name":"Shi Fang","orcid":"0000-0001-7095-6997","position":1,"is_corresponding":false},{"id":799666,"name":"Ko‐Ting Lu","orcid":null,"position":2,"is_corresponding":false},{"id":902962,"name":"Gaurav Kumar","orcid":"0000-0003-2075-9244","position":3,"is_corresponding":false},{"id":370964,"name":"John J. Reho","orcid":"0000-0003-0981-3027","position":4,"is_corresponding":false},{"id":902961,"name":"Daniel Brozoski","orcid":"0009-0006-1724-9437","position":5,"is_corresponding":false},{"id":908472,"name":"Adokole J Otanwa","orcid":null,"position":6,"is_corresponding":false},{"id":525593,"name":"Chunyan Hu","orcid":"0000-0002-8673-3859","position":7,"is_corresponding":false},{"id":490955,"name":"Anand R. Nair","orcid":"0000-0002-4067-1306","position":8,"is_corresponding":false},{"id":902963,"name":"Kelsey K. Wackman","orcid":"0000-0002-8253-6989","position":9,"is_corresponding":false},{"id":491534,"name":"Larry N Agbor","orcid":null,"position":10,"is_corresponding":false},{"id":370966,"name":"Justin L. Grobe","orcid":"0000-0001-9737-0873","position":11,"is_corresponding":false},{"id":446759,"name":"Curt D. Sigmund","orcid":"0000-0002-1453-0921","position":12,"is_corresponding":false},{"id":399576,"name":"Jing Wu","orcid":"0000-0003-2013-2863","position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":null,"created_at":"2026-07-19T00:25:34.440699Z","pmid":"35493997","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":[]}