Hyperuricemia impairs endothelial function through SMS2-dependent activation of the endoplasmic reticulum stress response.

Hyperuricemia is a recognized risk factor for cardiovascular diseases, including peripheral arterial disease (PAD), though molecular mechanisms linking uric acid to endothelial dysfunction remain unclear. This study investigates the role of sphingomyelin synthase 2 (SMS2) and endoplasmic reticulum (ER) stress in uric acid-induced endothelial impairment. Human umbilical vein endothelial cells were exposed to physiologically relevant concentrations of uric acid, with SMS2 function modulated through siRNA knockdown and ER stress inhibited using 4-phenylbutyric acid. Uric acid exhibited concentration-dependent cytotoxicity (IC50 ∼ 9 mg/dL) and significantly upregulated SMS2 expressions. At this concentration, uric acid significantly increased apoptosis, impaired migratory capacity, and diminished angiogenic potential (p < 0.01). These functional deficits coincided with marked elevation of ER stress markers and intracellular calcium disruption. Notably, both SMS2 knockdown and ER stress inhibition substantially reversed these uric acid-induced endothelial dysfunctions, restoring cell survival, migration, and angiogenic capacity while normalizing ER stress markers and calcium homeostasis (p < 0.01). These findings identify SMS2 as a potential therapeutic target for vascular complications in hyperuricemia and suggest ER stress modulators may protect against uric acid-induced endothelial damage.