Multiomics Profiling of Extracellular Vesicles Supports Their Involvement in Endothelial Senescence-Associated...

Area of Science:

• Vascular Biology
• Cellular Senescence
• Neurodegenerative Disease Pathogenesis

Background:

• Endothelial cell dysfunction is common in aging-related diseases like Alzheimer's disease (AD) and AD-related dementias (ADRD).
• The precise mechanisms by which endothelial dysfunction contributes to AD/ADRD pathogenesis remain unclear.
• A hypothesis suggests extracellular vesicles (EVs) from senescent vascular endothelial cells may drive this dysfunction.

Purpose of the Study:

• To investigate the molecular cargo of EVs released from senescent versus non-senescent human coronary artery endothelial cells (HCAECs).
• To determine if senescent endothelial cell-derived EVs (SEN-ECEVs) contain bioactive molecules linked to vascular dysfunction and AD/ADRD pathology.

Main Methods:

• Isolation and characterization of EVs from early passage (non-senescent) and late passage (senescent) HCAECs from multiple donors.
• Proteomic and miRNA profiling of isolated EVs.
• Bioinformatic analysis (FunRich gene ontology) to compare functional enrichment between non-senescent and senescent ECEVs.

Main Results:

• Replicative senescence altered EV abundance and molecular content, independent of EV size.
• SEN-ECEVs showed differential expression of unique proteins and miRNAs involved in cell adhesion, barrier integrity, signaling, endothelial-mesenchymal transition, and senescence.
• The most upregulated miRNA in SEN-ECEVs was miR-181a-5p (>5-fold increase).
• SEN-ECEV proteomes indicated involvement in pro-inflammatory pathways associated with senescence and the senescence-associated secretory phenotype (SASP).

Conclusions:

• Senescent endothelial cell-derived EVs (SEN-ECEVs) are enriched with bioactive molecules.
• These molecules are implicated in senescence-associated vascular dysfunction, blood-brain barrier impairment, and AD/ADRD pathology.
• SEN-ECEVs may play a significant role in the pathogenesis of vascular dysfunction contributing to AD/ADRD.