Macrophage-Derived Extracellular Particles Conditioned by Vicenin-2 and Advanced Glycation End-Products Reduce TNF-α-Induced ICAM-1 and VCAM-1 Transcript Expression in Human Endothelial Cells

The contribution of macrophage-mediated inflammation to endothelial dysfunction and atherosclerosis has been recognised for several decades. More recent evidence has implicated cell-derived mediators—extracellular particles and vesicles—as central to the intercellular crosstalk that sustains this inflammatory milieu. Extracellular particles (EPs) encompass all structures released by cells into the extracellular space, whereas extracellular vesicles (EVs) represent the subset enclosed by a lipid bilayer membrane and incapable of self-replication. The glycosidic flavonoid Vicenin-2 (V-2) has demonstrated immune-regulatory properties in macrophages; however, its capacity to modulate EP-mediated endothelial responses remains an emerging area of research. This study aimed to determine the effect of V-2 on the release of EPs from differentiated THP-1 macrophages (dTHP-1) stimulated with an advanced glycation end product (AGE; gBSA), and to determine whether these particles alter endothelial cell inflammatory gene expression. Human umbilical vein endothelial cells (HUVECs) were primed by incubating cells with the dTHP-1-derived EPs and subsequently stimulated with tumour necrosis factor-α (TNF-α). The mRNA expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) was assessed by Reverse Transcription-Polymerase Chain Reaction. EPs derived from V-2-conditioned dTHP-1 cells significantly reduced TNF-α-induced ICAM-1 expression in HUVECs (p < 0.001), while EPs from V-2 + gBSA-conditioned cells additionally reduced TNF-α-induced VCAM-1 transcript levels (p < 0.001) and produced a non-significant reduction in MCP-1 (p = 0.16). These protective effects were EP-mediated and were not recapitulated by direct V-2 treatment at equivalent concentrations. Although further mechanistic investigation is required, these data support a novel role for macrophage-conditioned EPs in mitigating AGE-driven endothelial dysfunction and highlight V-2 as a candidate agent for modulating EP-mediated vascular inflammation in the context of diabetic vasculopathy.