A, The network of 50 overlapping KEGG, Reactome, and BioCarta pathways that were significantly-enriched in the proteome and gene targets of miRs altered by disease in both intact carotid artery and aortic valve tissue EVs (n=6 normal carotid arteries, n=4 diseased carotid artery atherosclerotic plaques, n=6 normal aortic valves, n=4 diseased calcified aortic valves). Pathways are nodes (node size corresponds to -log(q-value)) and shared detected genes between pathways are edges (edge thickness matches the Jaccard index of overlap between detected genes of the two connected pathway nodes). B, Louvain clustering revealed 4 distinct annotations shared by disease-altered cardiovascular tissue-derived EV cargoes, including modulation of intracellular signaling cascades and cell cycle regulation and apoptosis. Pathway network betweenness-centrality scores (inset) implicate estrogen/epidermal growth factor signaling as a key common molecular constituent of tissue EVs.