The PVAT-MAMs Axis in Atherosclerosis: A Hypothesis-Driven Cross-Scale Conceptual Framework

Atherosclerosis (AS) is the leading cause of cardiovascular disease worldwide, yet its clinical heterogeneity and close association with metabolic disorders are not fully explained by the classical "endothelial injury-lipid deposition-inflammatory amplification" paradigm. In this review, we introduce the PVAT-MAMs axis as a hypothesis-driven, cross-scale conceptual framework linking extravascular metabolic dysfunction to intracellular stress signaling in vascular cells. We propose that, under metabolic stress, dysfunctional perivascular adipose tissue (PVAT) may influence mitochondria-associated endoplasmic reticulum membranes (MAMs) via the release of inflammatory, lipotoxic, and oxidative mediators. Accumulating experimental and associative evidence suggests that perturbation of MAMs is associated with dysregulated calcium handling, lipid metabolism, inflammatory signaling, and redox imbalance, processes implicated in AS progression. Although direct causal relationships remain to be fully established. By synthesizing current findings, this framework provides an integrative perspective on disease heterogeneity and highlights testable pathogenic nodes spanning from PVAT to subcellular MAMs. Finally, we discuss how this conceptual axis may inform hypothesis-driven therapeutic strategies. Importantly, the PVAT-MAMs axis is presented as a hypothesis-driven conceptual model rather than an established signaling pathway, and its mechanistic architecture requires rigorous experimental and translational validation.