Spatial architecture of atherosclerotic plaques: coordinating immune responses through mechanotransduction and...

Atherosclerosis is a progressive inflammatory vascular disease, and its acute clinical consequences-myocardial infarction and ischemic stroke-are the principal cause of cardiovascular mortality globally. Plaque rupture, driven by dysregulated immune activity within the plaque microenvironment, is the immediate precipitant of acute cardiovascular events. Single-cell RNA sequencing, spatial transcriptomics, and high-resolution mechanobiology have shown that atherosclerotic plaques are spatially organised structures in which functionally divergent cell populations occupy the fibrous cap, necrotic core, shoulder region, and neovascularisation zone-a heterogeneity organised by two regulatory axes: mechanotransduction and vesicular trafficking. This review elucidates how the mechano-vesicular dual-axis shapes the plaque immune microenvironment and drives the transition from stable to vulnerable plaque phenotype, and assesses the translational potential of the framework for precision diagnostics and therapeutics. We here formally propose the Mechano-Vesicular Dual-Axis (MVDA) model as a unifying conceptual framework for plaque immune microenvironment organisation, defined by three constitutive elements: (i) a mechanotransduction axis converting hemodynamic and matrix-stiffness cues into intracellular signaling; (ii) a vesicular trafficking axis propagating mechanically-encoded information across cells; and (iii) bidirectional coupling through shared signaling nodes (KLF2/4, YAP/TAZ, NF-κB, PI3K/Akt/mTOR). To our knowledge, this is the first explicit integration of these two regulatory axes into a single testable framework for plaque spatial biology. Oscillatory shear stress and progressive matrix stiffening reprogramme endothelial cells, macrophages, and vascular smooth muscle cells through mechanosensors including Piezo1, integrins, and YAP/TAZ, driving pro-inflammatory gene programmes and spatially directed immune cell migration. Extracellular vesicles (EVs) generated under distinct mechanical stimuli carry bioactive cargo-including miR-155, miR-146a, oxidised phospholipids, and damage-associated molecular patterns-that establishes paracrine and long-range intercellular communication networks propagating mechanical activation signals. The two axes are connected through shared signaling nodes (KLF2/4 as an upstream flow-sensitive gate; YAP/TAZ and NF-κB as parallel effectors; PI3K/Akt/mTOR as vesicular output controllers). Dysregulation manifests as elevated pro-inflammatory EV output, macrophage and T cell accumulation at the shoulder region, impaired efferocytosis, and progressive fibrous cap thinning, marking the mechanistic transition toward the vulnerable plaque phenotype. The MVDA model suggests a move from systemic pharmacological intervention toward spatially precise targeting of mechanically high-risk microregions. Translational candidates include Piezo1 antagonists, YAP/TAZ inhibitors delivered via biomimetic nanoparticles, engineered M2 macrophage-derived EVs, and circulating EV-encapsulated miRNA panels as non-invasive biomarkers of plaque vulnerability. The MVDA model's mechano-immune scaffold is substantially supported by human data; its vesicular reverse-coupling claims remain forward-looking and await in vivo genetic validation. Addressing methodological challenges-real-time mechanical signal quantification, standardised EV tracking, and the murine-to-human translational gap-will be central to the next phase of work.