Work

Hypobaric hypoxia-driven energy metabolism disturbance facilitates vascular endothelial dysfunction

Year: 2025

Type: article

Abstract: Hypobaric hypoxia in plateau environments inevitably disrupts metabolic homeostasis and contributes to high-altitude diseases. Vascular endothelial cells play a crucial role in maintaining vascular homeostasis. However, it remains unclear whether hypoxia-mediated changes in energy metabolism compromise vascular system stability and function. Through integrated transcriptomic and targeted metabolomic analyses, we identified that hypoxia induces vascular endothelial dysfunction via energy metabolism dysregulation. Specifically, hypoxia drives a metabolic shift toward glycolysis over oxidative phosphorylation in vascular endothelial cells, resulting in excessive lactate production. This lactate overload triggers PKM2 lactylation, which stabilizes PKM2 by inhibiting ubiquitination, forming a feedforward loop that exacerbates mitochondrial collapse and vascular endothelial dysfunction. Importantly, blocking the pyruvate-lactate axis helps maintain the balance between glycolysis and oxidative phosphorylation, thereby protecting vascular endothelial function under hypoxic conditions. Our findings not only elucidate a novel mechanism underlying hypoxia-induced vascular damage but also highlight the pyruvate-lactate axis as a potential therapeutic target for preventing vascular diseases in both altitude-related and pathological hypoxia.

Source: Redox Biology

DOI: 10.1016/j.redox.2025.103675