Hypobaric hypoxia-driven energy metabolism disturbance facilitates vascular endothelial dysfunction

Area of Science:

• Physiology
• Molecular Biology
• Altitude Medicine

Background:

• Plateau environments cause hypobaric hypoxia, disrupting metabolic homeostasis and contributing to altitude diseases.
• Vascular endothelial cells are vital for vascular homeostasis, but hypoxia's impact on their energy metabolism and function is not fully understood.

Purpose of the Study:

• To investigate how hypoxia-induced energy metabolism changes affect vascular endothelial cell stability and function.
• To identify the molecular mechanisms linking hypoxia, metabolism, and vascular dysfunction.

Main Methods:

• Integrated transcriptomic and targeted metabolomic analyses were employed.
• Investigated the role of lactate production and PKM2 lactylation in hypoxia-induced vascular endothelial dysfunction.

Main Results:

• Hypoxia shifts endothelial cell metabolism towards glycolysis, increasing lactate production.
• Lactate overload triggers PKM2 lactylation, stabilizing PKM2 and exacerbating mitochondrial collapse and vascular dysfunction.
• Blocking the pyruvate-lactate axis preserves endothelial function under hypoxia.

Conclusions:

• Hypoxia induces vascular endothelial dysfunction through energy metabolism dysregulation, specifically via the pyruvate-lactate-PKM2 axis.
• The pyruvate-lactate axis represents a potential therapeutic target for preventing vascular diseases in hypoxic conditions.