ERK3 regulates metabolic memory-related arterial endothelial dysfunction through glutamate

Endothelial dysfunction persisting after glucose normalization, termed metabolic memory, constitutes a primary driver of diabetic vascular complications, yet the underlying mechanisms remain incompletely understood. The atypical mitogen‑activated protein kinase ERK3 has been implicated in metabolic regulation, but its role in the vascular endothelium under diabetic conditions is unknown. We found that the protein levels of ERK3 in endothelial cells were markedly attenuated following high glucose exposure and failed to rebound upon subsequent glucose normalization. Integrated metabolomic profiling coupled with downstream experiments revealed that ERK3 regulated NO through glutamate-mGluR2 pathway. Endothelial-specific ERK3 knockout aggravated arterial endothelial injury in db/db mice with or without insulin treatment, which can be blocked by mGluR2 inhibitors. Our findings identify ERK3 as a critical regulator of endothelial metabolic memory via the glutamate‑mGluR2‑NO pathway. This novel mechanism expands the current understanding of metabolic memory and highlights ERK3 and its downstream glutamate axis as potential therapeutic targets for preventing or reversing diabetic vascular complications.