A review of the link between the lactate-GPR81 axis and mitochondrial angiopathy in MELAS based on imaging characteristics.

The differential diagnosis between Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) and acute ischemic stroke (AIS) is frequently confounded by the profound vascular heterogeneity inherent to MELAS, exemplified by phenomena such as the vessel flow-void sign (VFVS). This review first outlines the imaging hallmarks that distinguish MELAS from acute ischemic stroke, then interrogates the ostensible paradox between the systemic nitric oxide (NO) deficiency in MELAS and the localized vasodilation manifested as VFVS. We posit that lactate accumulation, a metabolic hallmark of the disease, is a principal yet underappreciated driver of this vascular phenotype. To address this mechanistic gap, we propose a conceptual framework centered on the G-protein-coupled lactate receptor 81 (GPR81). We hypothesize that the lactate-GPR81 signaling axis within the cerebral microvasculature constitutes a key pathway through which lactate modulates vascular smooth muscle cell phenotypic switching, angiogenesis, and microenvironmental remodeling, thereby orchestrating the unique vascular pathology of MELAS. While the precise mechanisms remain debated, we contend that a focus on mitochondrial vasculopathy is fundamental to elucidating the vascular heterogeneity in MELAS. By proposing the lactate-GPR81 axis as a central mediator, this perspective offers a refined conceptual framework to reorient future empirical investigation toward the development of diagnostic and therapeutic strategies that target this critical, albeit contested, vascular pathology.