{"doi":"10.1101/2023.04.15.536809","title":"Loss of presenilin-1 in smooth muscle cells ameliorates elastin aortopathy","abstract":"Abstract Smooth muscle cell (SMC) accumulation is central to the pathogenesis of elastin-defective arterial diseases, such as atherosclerosis, pulmonary hypertension and supravalvular aortic stenosis (SVAS). We previously demonstrated that elastin insufficiency activates the Notch pathway in aortic SMCs, resulting in hypermuscularization. Activation of Notch is catalyzed by the enzyme gamma-secretase, but the role of specific catalytic subunits PSEN-1 or PSEN-2 in elastin aortopathy is not defined. This study utilizes genetic approaches to query the role of PSEN-1/2 in the pathogenesis of elastin mutant mice, which model human SVAS. Although endothelial cell-specific Psen1 deletion does not improve elastin aortopathy, deletion of either Psen1 in SMCs or Psen2 globally attenuates Notch downstream gene expression and SMC proliferation, mitigating aortic disease. With SMC-specific Psen1 deletion in elastin nulls, these rescue effects are more robust and in fact, survival is increased. On the background of Psen1 deletion in SMCs, global Psen2 deletion yields additional benefits in regard to elastin aortopathy. Finally, SMC deletion of Psen1 also attenuates hypermuscularization in newborns heterozygous for the elastin null gene, which genetically mimics SVAS. Taken together, these findings put forth SMC PSEN-1 as a potential therapeutic target in elastin aortopathy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":406445,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9556,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":625114,"name":"Jui M. Dave","orcid":"0000-0002-5448-4798","position":1,"is_corresponding":false},{"id":1126384,"name":"Freddy Duarte Lau","orcid":"0000-0002-7394-5596","position":2,"is_corresponding":false},{"id":580265,"name":"Daniel M. Greif","orcid":"0000-0002-9842-3751","position":3,"is_corresponding":false},{"id":873034,"name":"Junichi Saito","orcid":"0000-0002-4297-727X","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T01:21:03.432924Z","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,"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":[]}