{"doi":"10.1101/2020.04.02.022525","title":"Conserved and Divergent Modulation of Calcification in Atherosclerosis and Aortic Valve Disease by Tissue Extracellular Vesicles","abstract":"Abstract Background Fewer than 50% of patients develop calcification of both atherosclerotic plaques and aortic valves, implying differential pathogenesis. While circulating extracellular vesicles (EVs) act as biomarkers of cardiovascular diseases, tissue-entrapped EVs associate with early mineralization, but their contents, function, and contributions to disease remain unknown. Results Global proteomics of human carotid artery endarterectomies and calcified aortic valves from a total of 27 donors/patients revealed significant over-representation of proteins with vesicle-associated pathways/ontologies common to both diseases. We exploited enzymatic digestion, serial (ultra)centrifugation and OptiPrep density-gradient separation to isolate EV populations from diseased arteries and valves. Mass spectrometry found 22 EV marker proteins to be highly enriched in the four least-dense OptiPrep fractions while extracellular matrix proteins predominated in denser fractions, as confirmed by CD63 immunogold electron microscopy and nanoparticle tracking analysis. Proteomics and miRNA-sequencing of OptiPrep-enriched tissue EVs quantified 1,104 proteins and 123 miR cargoes linked to 5,182 target genes. Pathway networks of proteins and miR targets common to artery and valve tissue EVs revealed a shared regulation of Rho GTPase and MAPK intracellular signaling cascades. 179 proteins and 5 miRs were significantly altered between artery and valve EVs; multi-omics integration determined that EVs differentially modulated cellular contraction and p53-mediated transcriptional regulation in diseased vascular vs. valvular tissue. Conclusions Our findings delineate a strategy to isolate, purify, and study protein and RNA cargoes from EVs entrapped in fibrocalcific tissues. Multi-omics and network approaches implicated tissue-resident EVs in human cardiovascular disease.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":120875,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9477,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":559213,"name":"Fabrizio Buffolo","orcid":"0000-0001-9363-0199","position":1,"is_corresponding":false},{"id":559214,"name":"Arda Halu","orcid":"0000-0001-6217-790X","position":2,"is_corresponding":false},{"id":559215,"name":"Florian Schlotter","orcid":"0000-0003-4840-1172","position":3,"is_corresponding":false},{"id":364516,"name":"Hideyuki Higashi","orcid":"0000-0002-8286-8190","position":4,"is_corresponding":false},{"id":178250,"name":"Lorena Pantano","orcid":"0000-0002-3859-3249","position":5,"is_corresponding":false},{"id":452148,"name":"Louis Saddic","orcid":null,"position":6,"is_corresponding":false},{"id":525063,"name":"Samantha K. Atkins","orcid":"0000-0002-4517-8991","position":7,"is_corresponding":false},{"id":559216,"name":"Maximillian A. Rogers","orcid":"0000-0001-9277-3200","position":8,"is_corresponding":false},{"id":559217,"name":"Tan Pham","orcid":"0000-0002-0381-1365","position":9,"is_corresponding":false},{"id":265384,"name":"Eugenia Shvartz","orcid":null,"position":10,"is_corresponding":false},{"id":266547,"name":"Galina K. Sukhova","orcid":"0000-0002-1421-9455","position":11,"is_corresponding":false},{"id":559218,"name":"Silvia Monticone","orcid":"0000-0002-7322-2005","position":12,"is_corresponding":false},{"id":312192,"name":"Giovanni Camussi","orcid":"0000-0003-2795-232X","position":13,"is_corresponding":false},{"id":88790,"name":"Simon C. Body","orcid":"0000-0001-6721-7050","position":14,"is_corresponding":false},{"id":521215,"name":"Jochen D. Muehlschlegel","orcid":"0000-0002-6209-7253","position":15,"is_corresponding":false},{"id":364514,"name":"Sasha A. Singh","orcid":"0000-0003-0929-3164","position":16,"is_corresponding":false},{"id":364518,"name":"Masanori Aikawa","orcid":"0000-0002-9275-2079","position":17,"is_corresponding":false},{"id":305056,"name":"Elena Aïkawa","orcid":"0000-0001-7835-2135","position":18,"is_corresponding":false},{"id":559212,"name":"Mark C. Blaser","orcid":"0000-0002-3923-9786","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-18T23:14:38.147936Z","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":[]}