Endothelial GABA protects against aortic dissection by inhibiting endothelial and mitochondrial dysfunction and maintaining vascular homeostasis

Thoracic aortic dissection (TAD) is a highly lethal vascular condition closely associated with endothelial cell (EC) dysfunction. γ-Aminobutyric acid (GABA) can be synthesized in ECs and modulate cell functions; however, its underlying roles in TADs are unclear. Untargeted metabolomics revealed that GABA levels are decreased in the aortic intima of TAD patients and that GABA is a hub metabolite involved in TAD pathogenesis. To investigate the role of endothelial GABA in TAD progression, mice with EC-specific GAD1 deletion or overexpression were generated via AAV infection, and a TAD model was induced. Both endogenous and exogenous GABA attenuate the development and incidence of TAD by reducing endothelial dysfunction and inflammatory infiltration. Mechanistically, GABA attenuated oxidative stress-induced endothelial dysfunction by inhibiting MAPK/c-FOS signaling pathway activation via GABBR2-mediated mitochondrial homeostasis. Moreover, EC-derived GABA protected vascular SMCs from inflammation-induced disturbances in homeostasis by modulating Notch3 protein expression. Plasma GABA levels are lower in TAD patients than in healthy controls, as determined by ELISA, and correlation analysis revealed that decreased plasma GABA levels are associated with an increased risk of aortic dissection. Diagnostic models for early TAD diagnosis based on plasma GABA levels were constructed and found to be highly effective. These findings demonstrated the substantial benefits of EC-derived GABA for vascular homeostasis by protecting ECs and SMCs from dysfunction and provided new insights for TAD intervention and prevention.