High Glucose Levels Promote Switch to Synthetic Vascular Smooth Muscle Cells via Lactate/GPR81

Area of Science:

• Cardiovascular Biology
• Metabolic Disease Research
• Vascular Cell Biology

Background:

• Hyperglycemia, lipotoxicity, and insulin resistance are linked to cardiac fibroblast activation and paracrine signaling.
• The impact of hyperglycemia on vascular smooth muscle cell (vSMC) phenotype remains underexplored.

Purpose of the Study:

• To investigate if contractile vSMCs adopt a synthetic phenotype under hyperglycemic conditions.
• To elucidate the role of lactate/GPR81 signaling in high glucose-induced vSMC changes.

Main Methods:

• Culturing vSMCs under high glucose conditions.
• Assessing vSMC phenotype markers, proliferation, and migration.
• Analyzing GPR81 expression in human diabetic blood vessels and mouse models.

Main Results:

• Contractile and synthetic vSMCs exhibit differential glucose consumption patterns.
• High glucose significantly increases vSMC expression of synthetic markers, collagen 1 production, proliferation, and migration.
• Lactate/GPR81 signaling mediates the promotion of the synthetic phenotype in vSMCs exposed to high glucose.
• Elevated GPR81 expression is observed in diabetic patients' blood vessels and in a high-glucose, high-lipid diet mouse model.

Conclusions:

• Vascular smooth muscle cells transition to a more synthetic phenotype in response to hyperglycemia.
• High glucose can initiate a vSMC-dependent cardiovascular disease pathway in diabetes through lactate/GPR81 signaling.