The Adipovascular Unit in Lipedema: A Framework for Regional Adipose Tissue Dysregulation

Abstract

Highlights What are the main findings? The adipovascular unit (AVU) is proposed as a system-level framework linking progenitor, vascular, immune, extracellular matrix, and adipocyte compartments in lipedema. The framework integrates regional susceptibility and reciprocal multicellular signaling while distinguishing lipedema-specific evidence from mechanisms inferred from general adipose-tissue biology. What are the implications of the main findings? The AVU model generates specific, falsifiable predictions that can be tested using spatial, single-cell, multicellular, and extracellular-vesicle approaches. The framework distinguishes regional lipedema biology from generic obesity-associated adipose dysfunction without proposing a new anatomical structure or an established causal lesion. Abstract Lipedema is a chronic, predominantly female disorder characterized by disproportionate regional expansion of subcutaneous adipose tissue, pain, tenderness, and easy bruising. Reported abnormalities involve adipocytes, stromal/progenitor cells, microvascular and immune compartments, extracellular matrix (ECM), and, variably, lymphatic function, but their causal and temporal relationships remain unresolved. Here, we propose the adipovascular unit (AVU) as a systems-level framework that links these compartments within a spatially organized regenerative niche. The conceptual advance is not the identification of a new anatomical structure, but the prediction that regional disease expression depends on reciprocal interactions among adipose stem and progenitor cells (ASPCs), endothelial and mural cells, immune populations, ECM, and mature adipocytes, rather than on a universal defect in any single cell type. We hypothesize that physiological female reproductive signals may expose a regionally susceptible AVU in which regenerative responses are inadequately constrained in space, magnitude, or duration. This framework also distinguishes lipedema from obesity-associated adipose dysfunction: lipedema is regionally patterned and may coexist with relatively preserved systemic metabolic function, whereas obesity-related adipose dysfunction is more closely linked to whole-body energy excess, ectopic fat, insulin resistance and cardiometabolic risk. Evidence demonstrated directly in lipedema is separated throughout from general adipose-tissue biology used to establish plausibility and from mechanisms that remain hypothetical. We derive falsifiable predictions involving depot-specific molecular states, endocrine context, multicellular cross-talk, extracellular-vesicle cargo and transfer, spatial biological boundaries, and persistence after stimulus withdrawal. Testing these predictions in paired-depot, spatially resolved and multicellular systems will determine whether AVU dysregulation is a causal organizing principle of lipedema or a descriptive consequence of established disease.