Punwasi, N. | bioRxiv Science

bioRxiv2024

Multi-omic Landscape of Extracellular Vesicles in Human Carotid Atherosclerotic Plaque Reveals Endothelial Communication Networks

Background: Carotid atherosclerosis is orchestrated by cell-cell communication that drives progression along a clinical continuum (asymptomatic to symptomatic). Extracellular vesicles (EVs) are cell-derived nanoparticles representing a new paradigm in cellular communication. Little is known about their biological cargo, cellular origin/destination, and functional roles in human atherosclerotic plaque. Methods: EVs were enriched via size exclusion chromatography from human carotid endarterectomy samples dissected into paired plaque and marginal zones (symptomatic n=16, asymptomatic n=13). EV cargos were assessed via whole transcriptome miRNA sequencing and mass spectrometry-based proteomics. EV multi-omics were integrated with bulk and single cell RNA-sequencing (scRNA-seq) datasets to predict EV cellular origin and ligand-receptor interactions, and multi-modal biological network integration of EV-cargo was completed. EV functional impact was assessed with endothelial angiogenesis assays. Results: Carotid plaques contained more EVs than adjacent marginal zones, with differential enrichment for EV-miRNAs and EV-proteins in key atherogenic pathways. EV cellular origin analysis suggested that tissue EV signatures originated from endothelial cells (EC), smooth muscle cells (SMC), and immune cells. Integrated tissue vesiculomics and scRNA-seq indicated complex EV-vascular cell communication that changed with disease progression and plaque vulnerability (i.e., symptomatic disease). Plaques from symptomatic patients, but not asymptomatic patients, were characterized by increased involvement of endothelial pathways and more complex ligand-receptor interactions, relative to their marginal zones. Plaque-EVs were predicted to mediate communication with ECs. Pathway enrichment analysis delineated an endothelial signature with roles in angiogenesis and neovascularization - well-known indices of plaque instability. This was validated functionally, wherein human carotid symptomatic plaque EVs induced sprouting angiogenesis in comparison to their matched marginal zones. Conclusion: Our findings indicate that EVs may drive dynamic changes in plaques through EV- vascular cell communication and effector functions that typify vulnerability to rupture, precipitating symptomatic disease. The discovery of endothelial-directed angiogenic processes mediated by EVs creates new therapeutic avenues for atherosclerosis.

cell biology↗

bioRxiv2023

Response diversity is key to buffer ecosystem productivity against multiple environmental change drivers

Evidence shows that biodiversity promotes primary productivity. However, it is unclear whether such biodiversity-productivity relationships persist under increasing numbers of environmental changes in the current Anthropocene. Here, we use theoretical and experimental approaches to demonstrate that variation in species responses to changing environments determines the ability of ecological communities to maintain productivity under multiple types of environmental change. Our theory shows that this response diversity determines whether biodiversity-productivity relationships are enhanced or impaired by environmental changes. Communities with high response diversity are expected not only to be productive in a particular environment but to maintain that productivity under multiple conditions. Nevertheless, our theory also predicts that such buffering effects fade with increasing negative environmental impacts on communities. Consistent with this prediction, our biodiversity experiment reveals impaired biodiversity-productivity relationships under multiple environmental change drivers with a negative mean impact. Our results suggest that, in the face of growing multiplicity of environmental changes, policies should encourage conservation of local biota, enabling communities to respond to unprecedented environments that may arise.

ecology↗