Multiomics of Tissue Extracellular Vesicles Identifies Unique Modulators of Atherosclerosis and Calcific Aortic Valve Stenosis
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Abstract
BACKGROUND: Fewer than 50% of patients who develop aortic valve calcification have concomitant atherosclerosis, implying differential pathogenesis. Although circulating extracellular vesicles (EVs) act as biomarkers of cardiovascular diseases, tissue-entrapped EVs are associated with early mineralization, but their cargoes, functions, and contributions to disease remain unknown. METHODS: Disease stage–specific proteomics was performed on human carotid endarterectomy specimens (n=16) and stenotic aortic valves (n=18). Tissue EVs were isolated from human carotid arteries (normal, n=6; diseased, n=4) and aortic valves (normal, n=6; diseased, n=4) by enzymatic digestion, (ultra)centrifugation, and a 15-fraction density gradient validated by proteomics, CD63-immunogold electron microscopy, and nanoparticle tracking analysis. Vesiculomics, comprising vesicular proteomics and small RNA-sequencing, was conducted on tissue EVs. TargetScan identified microRNA targets. Pathway network analyses prioritized genes for validation in primary human carotid artery smooth muscle cells and aortic valvular interstitial cells. RESULTS: Disease progression drove significant convergence ( P <0.0001) of carotid artery plaque and calcified aortic valve proteomes (2318 proteins). Each tissue also retained a unique subset of differentially enriched proteins (381 in plaques; 226 in valves; q<0.05). Vesicular gene ontology terms increased 2.9-fold ( P <0.0001) among proteins modulated by disease in both tissues. Proteomics identified 22 EV markers in tissue digest fractions. Networks of proteins and microRNA targets changed by disease progression in both artery and valve EVs revealed shared involvement in intracellular signaling and cell cycle regulation. Vesiculomics identified 773 proteins and 80 microRNAs differentially enriched by disease exclusively in artery or valve EVs (q<0.05); multiomics integration found tissue-specific EV cargoes associated with procalcific Notch and Wnt signaling in carotid arteries and aortic valves, respectively. Knockdown of tissue-specific EV-derived molecules FGFR2 , PPP2CA , and ADAM17 in human carotid artery smooth muscle cells and WNT5A , APP , and APC in human aortic valvular interstitial cells significantly modulated calcification. CONCLUSIONS: The first comparative proteomics study of human carotid artery plaques and calcified aortic valves identifies unique drivers of atherosclerosis versus aortic valve stenosis and implicates EVs in advanced cardiovascular calcification. We delineate a vesiculomics strategy to isolate, purify, and study protein and RNA cargoes from EVs entrapped in fibrocalcific tissues. Integration of vesicular proteomics and transcriptomics by network approaches revealed novel roles for tissue EVs in modulating cardiovascular disease.
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Of the 261 prioritized genes, 127 (47%) were expressed in the AV as evidenced by a transcript or protein product observed in human AV proteomics or transcriptomics or by genetically predicted expression substantially modifying AS risk in TWAS using AV tissue transcriptomes.
“Of the 261 prioritized genes, 127 (47%) were expressed in the AV as evidenced by having either a transcript or a protein product observed in proteomics or transcriptomic data of the human AV18,19 or with genetically predicted expression substantially modifying risk of AS in TWAS using AV tissue transcriptomes.”
From Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction (2026) · cites this paper as [18]
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The Role of Wnt/β-Catenin Pathway Mediators in Aortic Valve Stenosis
Khan, K., Yu, B., Kiwan, C. M., Shalal, Y., Filimon, S., Cipro, M., Shum‐Tim, D., Cecere, R., & Schwertani, A. G. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00862 · Cited by 31 · see citing works
Pathological Role of Receptor for Advanced Glycation End Products in Calcified Aortic Valve Stenosis
Saku, K., Tahara, N., Takaseya, T., Otsuka, H., Takagi, K., Shojima, T., Shintani, Y., Zaima, Y., Kikusaki, S., Fukuda, T., et al. (2020) · Journal of the American Heart Association · doi:10.1161/jaha.119.015261 · Cited by 26 · see citing works
Blaser, M. C., & Aïkawa, E. (2019) · Circulation Research · doi:10.1161/circresaha.119.314596 · Cited by 21 · see citing works
Self-citationZhu, X., Zhou, H., Yang, F., Zhang, H., & Ma, K. (2020) · The Journal of Gene Medicine · doi:10.1002/jgm.3274 · Cited by 20 · see citing works
Chen, H., Zhang, Z., Zhang, L., Wang, J., Zhang, M., & Zhu, B. (2018) · Brazilian Journal of Medical and Biological Research · doi:10.1590/1414-431x20186997 · Cited by 19 · see citing works
Xie, F., Li, F., Li, R., Liu, Z., Shi, J., Zhang, C., & Dong, N. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118086 · Cited by 19 · see citing works
Sphingosine 1-phosphate activation of ERM contributes to vascular calcification
Morris, T., Borland, S. J., Clarke, C. J., Wilson, C., Hannun, Y. A., Ohanian, V., Canfield, A. E., & Ohanian, J. (2017) · Journal of Lipid Research · doi:10.1194/jlr.m079731 · Cited by 19 · see citing works
Araya, H., Sepúlveda, H., Lizama, C. O., Vega, O. A., Jerez, S., Briceño, P., Thaler, R., Riester, S. M., Antonelli, M., Salazar‐Onfray, F., et al. (2018) · Journal of Cellular Biochemistry · doi:10.1002/jcb.26832 · Cited by 17 · see citing works
XINA: A Workflow for the Integration of Multiplexed Proteomics Kinetics Data with Network Analysis
Lee, L. H., Halu, A., Morgan, S., Iwata, H., Aikawa, M., & Singh, S. A. (2018) · Journal of Proteome Research · doi:10.1021/acs.jproteome.8b00615 · Cited by 16 · see citing works
Self-citationWnt Pathway Gene Expression Is Associated With Arterial Stiffness
Kuipers, A. L., Miljkovic, I., Barinas‐Mitchell, E., Nestlerode, C. S., Cvejkus, R., Wheeler, V. W., Zhang, Y., & Zmuda, J. M. (2020) · Journal of the American Heart Association · doi:10.1161/jaha.119.014170 · Cited by 16 · see citing works
Gao, L. P., Ji, Y. R., Lu, Y., Qiu, M., Shen, Y., Wang, Y., Kong, X., Shao, Y., Sheng, Y., & Sun, W. Y. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.791145 · Cited by 15 · see citing works
Li, Y., Cui, X., Tian, Y., Zhao, Y., Gao, H., Yao, D., & Liu, L. (2022) · Current Pharmaceutical Biotechnology · doi:10.2174/1389201023666220324123224 · Cited by 14 · see citing works
Induced pluripotent stem cell-derived smooth muscle cells to study cardiovascular calcification
Atkins, S. K., Sonawane, A. R., Brouwhuis, R., Barrientos, J., Ha, A. H., Rogers, M. A., Tanaka, T., Okui, T., Kuraoka, S., Singh, S. A., et al. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.925777 · Cited by 12 · see citing works
Self-citationLi, K., Chen, J., Li, Z. H., Zhan, J., Zhao, L., & He, Y. (2012) · Cardiovascular journal of South Africa/Cardiovascular journal of Southern Africa · doi:10.5830/cvja-2011-069 · Cited by 8 · see citing works
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Multi-Omics Approaches to Define Calcific Aortic Valve Disease Pathogenesis
Blaser, M. C., Kraler, S., Lüscher, T. F., & Aikawa, E. (2021) · Circulation Research · doi:10.1161/circresaha.120.317979 · Cited by 109 · see citing works
Self-citationHigh lipoprotein(a): Actionable strategies for risk assessment and mitigation
Reyes‐Soffer, G., Yeang, C., Michos, E. D., Boatwright, W., & Ballantyne, C. M. (2024) · American Journal of Preventive Cardiology · doi:10.1016/j.ajpc.2024.100651 · Cited by 83 · see citing works
“Both ASCVD and CAVS feature calcification, however, calcification of atherosclerotic plaque occurs relatively late in the disease process, whereas it features prominently in the earlier stages of CAVS and potentiates the progression of CAVS [69,71,72].”
BackgroundCarotid artery atherosclerosis: mechanisms of instability and clinical implications
Saba, L., Cau, R., Vergallo, R., Kooi, M. E., Staub, D., Faa, G., Congiu, T., Ntaios, G., Wasserman, B. A., Benson, J. C., et al. (2024) · European Heart Journal · doi:10.1093/eurheartj/ehae933 · Cited by 65 · see citing works
Prospects and challenges of tissue-derived extracellular vesicles
Lee, C. J., Ray, R. M., & Scott, T. A. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.06.025 · Cited by 54 · see citing works
“150 Ti-EVs have been implicated in other tissues with diverse roles such as placental Ti-EVs in preeclampsia, 151 or hepatic Ti-EVs in the progression of acute-to-chronic liver failure, 152 but these organs and pathologies are largely understudied.”
Chen, J., Ren, T., Xie, L., Hu, H., Li, X., Maitusong, M., Zhou, X., Hu, W., Xu, D., Qian, Y. H., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-44726-0 · Cited by 52 · see citing works
Calcific aortic stenosis: omics-based target discovery and therapy development
Blaser, M. C., Bäck, M., Lüscher, T. F., & Aikawa, E. (2025) · European Heart Journal · doi:10.1093/eurheartj/ehae829 · Cited by 45 · see citing works
“40 Vesiculomics techniques have also been applied to tissue-engineered, bio-mechanically relevant, multi-layered, 3D-bioprinted, VIC-laden hydrogel valve organoids as a means of benchmarking model performance against native human tissues.”
InfluentialSelf-citationHmadeh, S., Trimaille, A., Matsushita, K., Marchandot, B., Carmona, A., Zobairi, F., Sato, C., Kindo, M. J., Hoang, T. M., Toti, F., et al. (2024) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2024.02.012 · Cited by 39 · see citing works
Xiao, J., & Sluijter, J. P. G. (2025) · Nature Reviews Cardiology · doi:10.1038/s41569-025-01141-2 · Cited by 38 · see citing works
“analyses of human aortic valves and artery atherosclerotic plaques has uncovered unique EV constituents in tissues and cell type-specific regulatory factors involved in calcification, which could be considered as putative biomarkers of calcific aortic valves and atherosclerotic plaques 64 .”
2020 Jeffrey M. Hoeg Award Lecture
Aïkawa, E., & Blaser, M. C. (2020) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.120.314704 · Cited by 34 · see citing works
Self-citationCell-cell interactions in the heart: advanced cardiac models and omics technologies
Tan, S., Yang, J., Hu, S., & Lei, W. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-024-03982-z · Cited by 30 · see citing works
“In a recent study, Mark C. Blaser et al. conducted the proteomic comparison of human carotid plaques and calcified aortic valves, revealing that EV-mediated cell-cell communication may be involved in advanced cardiovascular calcification [121].”
BackgroundDirectional Endothelial Communication by Polarized Extracellular Vesicle Release
Raju, S., Botts, S. R., Blaser, M. C., Abdul-Samad, M., Prajapati, K., Khosraviani, N., Ho, T. W. W., Breda, L. C. D., Ching, C., Galant, N. J., et al. (2024) · Circulation Research · doi:10.1161/circresaha.123.322993 · Cited by 30 · see citing works
Self-citationClift, C. L., Blaser, M. C., Gerrits, W., Turner, M. E., Sonawane, A. R., Pham, T., Andresen, J. L., Fenton, O. S., Grolman, J. M., Campedelli, A., et al. (2024) · Science Advances · doi:10.1126/sciadv.adj9793 · Cited by 30 · see citing works
Self-citationCirculating Extracellular Vesicles in Cardiovascular Disease
Cappucci, I. P., Tremoli, E., Zavan, B., & Ferroni, L. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26146817 · Cited by 24 · see citing works
“Building on the understanding of miRNA involvement in AS, studies by Blaser et al. [72] have shown that miR-199b-5p and miR-381-3p levels decreased in plaque-derived EVs compared to normal controls.”
A roadmap towards manufacturing extracellular vesicles for cardiac repair
Louro, A. F., Meliciano, A., Alves, P. M., Costa, M. H., & Serra, M. (2024) · Trends in biotechnology · doi:10.1016/j.tibtech.2024.03.010 · Cited by 23 · see citing works
Zhao, Z., Dong, Y., Zhao, Z., Xiahou, Z., & Sun, C. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1569988 · Cited by 23 · see citing works
Engineering extracellular vesicles for targeted therapeutics in cardiovascular disease
Fu, E., Pan, K., & Li, Z. (2024) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2024.1503830 · Cited by 22 · see citing works
Multi-omics analysis identified extracellular vesicles as biomarkers for cardiovascular diseases
Ke, M., Meng, F., Wu, Y., & Lin, L. (2024) · Talanta · doi:10.1016/j.talanta.2024.126710 · Cited by 22 · see citing works
Amyloid and collagen templates in aortic valve calcification
Jayaraman, S., Narula, N., Narula, J., & Gursky, O. (2024) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2024.04.015 · Cited by 21 · see citing works
Vascular calcification: High incidence sites, distribution, and detection
Gui, Z., Shao, C., Zhan, Y., Wang, Z., & Li, L. (2024) · Cardiovascular Pathology · doi:10.1016/j.carpath.2024.107667 · Cited by 20 · see citing works
Precision cardiovascular medicine: shifting the innovation paradigm
Aikawa, M., Sonawane, A. R., Chelvanambi, S., Asano, T., Halu, A., Matamalas, J. T., Singh, S. A., Uchida, S., Aïkawa, E., Arenas, À., et al. (2025) · Frontiers in Science · doi:10.3389/fsci.2025.1474469 · Cited by 22 · see citing works
Self-citationAdvancing Extracellular Vesicle Research: A Review of Systems Biology and Multiomics Perspectives
Kemunto, G., Ghadami, S., & Dellinger, K. (2025) · PROTEOMICS · doi:10.1002/pmic.70066 · Cited by 20 · see citing works
“For example, seminal studies combining tissue EV proteomics and RNA-seq via network models have identified disease-specific EV cargo associated with cardiovascular calcification pathways, uncovering functional links to Wnt and Notchsignalinginvascularversusvalvulardisease[17].”
Network-guided multiomic mapping of aortic valve calcification
Blaser, M. C., Kraler, S., Lüscher, T. F., & Aikawa, E. (2023) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.122.318334 · Cited by 16 · see citing works
Self-citationRaju, S., Turner, M. E., Cao, C., Abdul-Samad, M., Punwasi, N., Blaser, M. C., Cahalane, R. M. E., Botts, S. R., Prajapati, K., Patel, S., et al. (2025) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.124.322324 · Cited by 15 · see citing works
Self-citationCai, J., Ge, X., Lu, S., Wang, Y., Cui, H., Zhan, R., Su, S., Shan, W., Cai, Z., Wu, C., et al. (2024) · Advanced Functional Materials · doi:10.1002/adfm.202406192 · Cited by 13 · see citing works
Turner, M. E., Bartoli‐Leonard, F., & Aïkawa, E. (2022) · Immunological Reviews · doi:10.1111/imr.13134 · Cited by 14 · see citing works
Self-citationSmall, A. M., Yang, T.-Y., Itoh, S., Thériault, S., Dufresne, L., Kurosawa, R., Komuro, I., Matsuda, K., Vy, H. M. T., Farber-Eger, E. H., et al. (2026) · Nature Genetics · doi:10.1038/s41588-025-02417-6 · Cited by 12 · see citing works
“We observed that silencing of LTBP4 in human VICs suppressed calcification in vitro.”
InfluentialSelf-citationAtherosclerosis, calcific aortic valve disease and mitral annular calcification: same or different?
Hafiane, A., Pisaturo, A., Favari, E., & Bortnick, A. E. (2024) · International Journal of Cardiology · doi:10.1016/j.ijcard.2024.132741 · Cited by 14 · see citing works
Viegas, C., Carreira, J., Maia, T. M., Macedo, A. L., Matos, A., Neves, J., & Simes, D. C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252212406 · Cited by 11 · see citing works
“This approach enables the digestion of the collagen-rich ECM characteristic of VSMCs, maintaining cell integrity and minimizing co-isolation of intracellular vesicles or membranous particles [29].”
InfluentialExtracellular Vesicles in Atherosclerosis: From Pathogenesis to Theranostic Applications
Fang, F., Yang, H., Wang, X., Zhao, T., Zhao, P., & Liu, X. (2025) · Small · doi:10.1002/smll.202504761 · Cited by 11 · see citing works
Challenges and Opportunities in Valvular Heart Disease: From Molecular Mechanisms to the Community
Aikawa, E. R., Blaser, M. C., Singh, S. A., Levine, R. A., & Yacoub, M. H. (2024) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.123.319563 · Cited by 11 · see citing works
Self-citationWang, Y., Hu, M., Spanos, M., Xu, S., Song, J., Li, G., Crețoiu, D., & Xiao, J. (2026) · 中国科学通报：英文版 · doi:10.1016/j.scib.2026.01.067 · Cited by 10 · see citing works
Distinct Genetic Risk Profile in Aortic Stenosis Compared With Coronary Artery Disease
Trenkwalder, T., Maj, C., Al‐Kassou, B., Dębiec, R., Doppler, S. A., Musameh, M. D., Nelson, C. P., Dasmeh, P., Grover, S., Knoll, K., et al. (2024) · JAMA Cardiology · doi:10.1001/jamacardio.2024.3738 · Cited by 9 · see citing works
Xu, X. J., Lu, T., Feng, Y., Cao, W., Liu, D., Gao, P., Ma, Y., Wang, Y., Yang, B., Chen, Y., et al. (2025) · MedComm · doi:10.1002/mco2.70220 · Cited by 9 · see citing works
Lipoprotein (a) in primary cardiovascular disease prevention is actionable today
Parcha, V., & Bittner, V. (2025) · American Heart Journal Plus Cardiology Research and Practice · doi:10.1016/j.ahjo.2025.100581 · Cited by 9 · see citing works
“Third, Lp(a) drives calcific remodeling of the aortic valve [17,21,30,61].”
Clift, C. L., Blaser, M. C., Bartoli‐Leonard, F., Schlotter, F., Higashi, H., Kuraoka, S., Kasai, T., Turner, M. E., Pham, T., Perez, K. A., et al. (2025) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.125.322560 · Cited by 7 · see citing works
Self-citationBaddour, T., Ninh, V. K., Gorashi, R. M., Peña, R., King, K. R., & Aguado, B. A. (2026) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.126.324694 · Cited by 8 · see citing works
Identification of hub genes in calcific aortic valve disease
Lai, Q., Zheng, J., Mou, J., Cui, C.-Y., Wu, Q., Rizvi, S., Zhang, Y., Li, T. M., Ren, Y.-B., Li, T. M., et al. (2024) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2024.108214 · Cited by 8 · see citing works
Progression of aortic stenosis after an acute myocardial infarction
Paquin, A., Marsit, O., Deschênes, V., Rouabhia, D., Hadjadj, S., Clisson, M., Robitaille, C., Aikawa, E. R., Levine, R. A., Pîbarot, P., et al. (2022) · Open Heart · doi:10.1136/openhrt-2022-002046 · Cited by 8 · see citing works
Self-citationExtracellular Vesicles From Chylomicron-Treated Endothelial Cells Drive Macrophage Inflammation
Tilp, A., Nasias, D., Carley, A., Park, M. Y., Mooring, A., Tirumalasetty, M. B., Abumrad, N. A., Wang, Y., Miao, Q., Lewandowski, E. D., et al. (2025) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.125.322712 · Cited by 7 · see citing works
Wilimski, R., Budzianowski, J., Łomiak, M., Olasińska‐Wiśniewska, A., Pieniak, K., Jędrzejczyk, S., Domaszk, O., Chudzik, M., Filipiak, K. J., Hiczkiewicz, J., et al. (2024) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-024-10521-x · Cited by 7 · see citing works
“Recent proteomics study highlighted tissue EVs as important drivers of aortic valve calcification – an important mechanism contributing to AS progression [12].”
Wen, H., Huang, R., Xu, X., Xiong, Z., Liu, M., Guo, Y., Zhuang, X., & Liao, X. (2024) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwae078 · Cited by 8 · see citing works
MicroRNAs regulate the vicious cycle of vascular calcification-osteoporosis in postmenopausal women
Wang, Q., Peng, F., Yang, J., Chen, X., Peng, Z., Zhang, M., Tang, D., Liu, J., & Zhao, H. (2024) · Molecular Biology Reports · doi:10.1007/s11033-024-09550-1 · Cited by 6 · see citing works
Non-Coding RNA Involved in the Pathogenesis of Atherosclerosis—A Narrative Review
Kiełbowski, K., Żychowska, J., Bakinowska, E., & Pawlik, A. (2024) · Diagnostics · doi:10.3390/diagnostics14171981 · Cited by 6 · see citing works
“Using disease-specific proteomics, the authors analyzed carotid endarterectomy specimens and demonstrated 80 differently enriched extracellular vesicle-associated miRNAs between artery atherosclerosis and valve stenosis [96].”
BackgroundCook‐Calvete, A., Delgado-Marín, M., Fernandez-Rodriguez, B. M., Zaragoza, C., & Saura, M. (2025) · Biomolecules · doi:10.3390/biom15111548 · Cited by 6 · see citing works
“For instance, EVs derived from calcified aortic valves are enriched in osteogenic proteins such as BMP-2 and Annexins, which drive calcification via activation of Wnt/ β -catenin and Notch pathways [4,5].”
InfluentialExtracellular Vesicles for Acute Care Testing: A Review of Potential Laboratory Applications
Mohapatra, N., Carney, R. P., Wang, A., Grimsrud, K., & Tran, N. K. (2025) · The Journal of Applied Laboratory Medicine · doi:10.1093/jalm/jfaf200 · Cited by 6 · see citing works
Spatially resolved profiling of extracellular vesicles in tissues with Spatial-EV-seq
Wen, Q., Xing, N., Lu, Y., Zhang, Q., Zha, Z., Zhao, H., Zhang, G.-B., Wu, Q., Liu, X. Y., Zhu, Z., et al. (2026) · Nature Biotechnology · doi:10.1038/s41587-026-03192-3 · Cited by 6 · see citing works
Novel Circulating Biomarkers in Aortic Valve Stenosis
Ong, J. Y.-S., Tan, S. M. L., Koh, A. S.-M., Kong, W. K. F., Sia, C., Yeo, T. C., Quek, S. C., & Poh, K. K. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26051902 · Cited by 6 · see citing works
“Notably, tissue-specific extracellular vesicles-derived molecules have been shown to modulate calcification in valvular interstitial cells and smooth muscle cells [127].”
Endogenously Gated DNA Walking Machine for Prescreened MicroRNA Detection in Extracellular Vesicles
Chen, W., Sun, J., Mao, Y., Tang, Y., Wang, J., & Liu, Z. (2024) · Analytical Chemistry · doi:10.1021/acs.analchem.3c05595 · Cited by 6 · see citing works
Passos, L. S. A., BECKER-GREENE, D. R., Bráulio, R., Le, T.-D., Gelape, C. L., de Almeida, L. F. R., Rocha, D. P. A., Gomes, C. A. P., Esteves, W. A. M., Passaglia, L. G., et al. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.804111 · Cited by 6 · see citing works
Self-citationLi, Y., Zhang, L., Wu, Y., Lü, W., Zhang, Z., Mo, H., Liu, Z., Wang, X., Shen, Y., & Zhu, H. (2024) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2024193 · Cited by 5 · see citing works
“The heart, a complex organ comprising diverse cell types, such as cardiomyocytes, endothelial cells, fibroblasts, and macrophages, releases EVs containing genetically regulated substances in re - sponse to various stresses and stimuli, thereby establishing intercellular homeostasis [11,12].”
CAP1: a novel extracellular vesicle marker linked to endothelial senescence in atherosclerosis
Hernández, I., Botana, L., Díez-Mata, J., Tesoro, L., Jiménez-Guirado, B., González-Cucharero, C., Alcharani, N., Zamorano, J. L., Saura, M., & Zaragoza, C. (2025) · Biology Direct · doi:10.1186/s13062-025-00646-7 · Cited by 4 · see citing works
“EVs are secreted in response to many pathological conditions, containing several cargo components [22], which may play a significant role in the progression of aging-related diseases, like Alzheimer’s disease [23], chronic kidney disease [24], and atherosclerosis [25].”
Khandagale, A. B., Corcoran, P., Dan, Y., Isaksson, A., James, S. K., Siegbahn, A., & Christersson, C. (2025) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2025.101327 · Cited by 4 · see citing works
Elevated miR-145/TLR4/NF-κB signaling correlates with myocardial PANoptosis in septic rats
Wang, Z., Shan, Y., Li, C., Liu, S., & Shan, L. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.153169 · Cited by 3 · see citing works
Amabile, N., Aïkawa, E., Dignat‐George, F., Boulanger, C. M., Yao, Y., & Leroyer, A. S. (2026) · European Heart Journal · doi:10.1093/eurheartj/ehag404 · Cited by 3 · see citing works
Self-citationGarcia, L. F. C., Wowk, P. F., & Albrecht, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25094761 · Cited by 3 · see citing works
“These analyses have played a critical role in multiomics experiments that use multiple assessments, enabling the detection of alterations that specific tests might not identify with the same precision [99].”
BackgroundWei, K., Cao, Y., Kong, X., Liu, C., & Gu, X. (2024) · Journal of Inflammation Research · doi:10.2147/jir.s462546 · Cited by 3 · see citing works
“6,7 Research has increasingly highlighted the role of specific immune cells and cytokines in AVC and CAS.”
BackgroundSivan, S., Vijayakumar, G., & Pillai, I. C. L. (2024) · Gene · doi:10.1016/j.gene.2024.149117 · Cited by 3 · see citing works
Wasserman, A. H., Abolibdeh, B., Hamdan, R., & Hong, C. C. (2025) · Current Treatment Options in Cardiovascular Medicine · doi:10.1007/s11936-025-01088-0 · Cited by 3 · see citing works
Wen, L.-Y., Qi, N., & Li, S. (2025) · Journal of Thrombosis and Thrombolysis · doi:10.1007/s11239-025-03112-3 · Cited by 2 · see citing works
Clift, C. L., Goudot, G., Bogut, G., Kasai, T., van Kampen, A., Pantaleão, A. N., Messas, E., Aikawa, M., Singh, S. A., Levine, R. A., et al. (2025) · Ultrasound in Medicine & Biology · doi:10.1016/j.ultrasmedbio.2025.06.026 · Cited by 2 · see citing works
Self-citationExtracellular Vesicles in Cardiovascular Diseases: Signaling, Biomarker, and Therapy
Chen, W., Zhu, X., Yu, S., & Ma, H. (2025) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-025-10706-y · Cited by 2 · see citing works
“However, pathologically activated SMCs secrete annexin/PS-enriched EVs that nucleate hydroxyapatite, directly driving microcalcification [95].”
Cook‐Calvete, A., Moreta, S., Delgado-Marín, M., Fernandez-Rodriguez, B. M., Zaragoza, C., & Saura, M. (2025) · European Journal of Clinical Investigation · doi:10.1111/eci.70147 · Cited by 2 · see citing works
“88,98,99 EVs can also transport regulatory miRNAs that fine-tune gene expression in target cells.”
Nguyen, T. H., Huynh, N. T., Niego, B., Hagemeyer, C. E., & Xu, R. (2026) · Small Structures · doi:10.1002/sstr.202500709 · Cited by 2 · see citing works
Parker, S. J., Mao, C., Caudell, D. L., Seals, A. L., Wang, Y., Green, T. D., McClung, J. M., Maxwell, J. T., Roddey, J. T., Shakeriastani, K., et al. (2026) · European Heart Journal · doi:10.1093/eurheartj/ehag166 · Cited by 2 · see citing works
Precision and network medicine in cardiovascular prevention and disease
Pandey, A. K., & Loscalzo, J. (2026) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2026.120743 · Cited by 2 · see citing works
Baddour, T., Ninh, V. K., Gorashi, R. M., Peña, R., King, K. R., & Aguado, B. A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.20.671175 · Cited by 2 · see citing works
“…biomarkers: [1] valvular interstitial cells (VICs) ( CLU, MGP, DCN, IGFBP7, PLA2G2A ), [2] macrophages ( CCL3, HLA-DRB1, CCL3L1, HLA-DRA, CCL4L2 ), [3] valvular endothelial cells (VECs) ( SERPINE1, IFI27, SAT1, CXCL2 ), and [4] T cells ( PTPRC, CDC42, CNOT6L, TMSB4X ) ( Figures 2E – 2F ).”
Disease Drivers in Aortic Stenosis vs Atherosclerosis
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Extracellular vesicle omics assisted disease management
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Lipidomic remodeling is associated with hemodynamic severity in calcific aortic valve stenosis
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- Authors
- Blaser, M. C., Buffolo, F., Halu, A., Turner, M. E., Schlotter, F., Higashi, H., Pantano, L., Clift, C. L., Saddic, L. A., Atkins, S. K., Rogers, M. A., Pham, T., Vromman, A., Shvartz, E., Sukhova, G. K., Monticone, S., Camussi, G., Robson, S. C., Body, S. C., Muehlschlegel, J. D., Singh, S. A., Aikawa, M., & Aikawa, E.
- Affiliations
- Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Department of Medicine (M.C.B., F.B., A.H., M.E.T., F.S., H.H., C.L.C., L.A.S., S.K.A., M.A.R., T.P., S.A.S., M.A., E.A.)
- Harvard University (US)
- Channing Division of Network Medicine, Department of Medicine (A.H., M.A.)
- University of Turin (IT)
- Beth Israel Deaconess Medical Center (US)
- Boston University (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Aikawa, Elena
- ORCID
- Blaser, Mark C.
- Buffolo, Fabrizio
- Halu, Arda
- Turner, Mandy E.
- Schlotter, Florian
- Higashi, Hideyuki
- Pantano, Lorena
- Clift, Cassandra L.
- Atkins, Samantha K.
- Rogers, Maximillian A.
- Pham, Tan
- Vromman, Amélie
- Sukhova, Galina K.
- Monticone, Silvia
- Camussi, Giovanni
- Robson, Simon C.
- Body, Simon C.
- Muehlschlegel, Jochen D.
- Singh, Sasha A.
- Aikawa, Masanori
- Aikawa, Elena
- Venue
- Circulation
- Published
- 2023-08-22
- Volume
- 148
- Issue
- 8
- Pages
- 661-678
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC10527599
- OpenAlex
- W4383710497
- Cited by
- 114
- References
- 92
- Citations by year
- 2026: 38 · 2025: 36 · 2024: 33 · 2023: 1 · 2022: 4 · 2021: 1 · 2020: 1
- FWCI
- 9.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Funders
- American Heart Association (18CSA34080399)
- Amgen
- AstraZeneca
- Sanofi
- Brigham and Women's Hospital
- Harvard University (UL 1TR002541)
- Harvard Catalyst (UL1TR002541, 1TR002541)
- Harvard T.H. Chan School of Public Health
- Regeneron Pharmaceuticals
- Ionis Pharmaceuticals
- IFM Therapeutics
- Kowa Company
- XBiotech
- Esperion Therapeutics
- National Institutes of Health (UL1TR002541, R01HL141719, HL080472, 1TR002541, HL134892)
- National Heart, Lung, and Blood Institute (K25HL150336, HL080472, R01HL150401, R01HL149998, R01HL136431, R01HL147095, R01HL080472, R01HL141917, R01HL134892)
- National Center for Advancing Translational Sciences (1TR002541)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Keywords
- atherosclerosis, calcific aortic stenosis, aortic valve calcification, carotid plaque, microRNA, Notch signaling, Wnt signaling, FGFR2, PPP2CA, ADAM17, Wnt5a, APP, APC, valvular interstitial cells, extracellular vesicle biomarkers, disease progression, mineralization, multi-omics integration
- MeSH terms
- Extracellular Vesicles, Multiomics, Aortic Valve, Aortic Valve Stenosis, Calcinosis, Cells, Cultured, Humans, MicroRNAs, Atherosclerosis, Wnt Signaling Pathway
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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