GPR39 Activation Attenuates AngII-Induced Abdominal Aortic Aneurysm by Suppressing ETS-1 Mediated VEGF-A/VEGFR2 Signalling

Abstract

Abdominal aortic aneurysm (AAA), a vascular condition that endangers life, is typified by the progressive weakening and dilation of the aortic wall. In its pathogenic process, oxidative stress and angiogenesis assume crucial functions. This research explored the function of G protein-coupled receptor 39 (GPR39) in angiotensin II (AngII)-induced AAA in ApoE−/− mice and its underlying mechanisms. A series of in vivo and in vitro experiments were performed, including AngII infusion-induced AAA in mice, histological analysis, ELISA, Western blotting, quantitative PCR, and angiogenic tube formation assays. GPR39 expression was significantly downregulated in arterial tissues of AngII-induced AAA mice, as evidenced by reduced mRNA and protein. Administration of the GPR39 agonist TC-G 1008 markedly attenuated AAA progression, reducing aneurysm incidence and size. Furthermore, TC-G 1008 alleviated oxidative stress through reducing the levels of malondialdehyde (MDA) and augmenting the activity of superoxide dismutase (SOD) as well as the levels of glutathione (GSH) in arterial tissues. TC-G 1008 also suppressed the vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGF-R2) expressions in both saline- and AngII-infused mice. In vitro, TC-G 1008 inhibited AngII-induced angiogenic tube formation in human umbilical vein endothelial cells (HUVECs) and downregulated VEGF-A/VEGFR2 signalling. Mechanistically, TC-G 1008 reduced the expression of the transcription factor Ets-related transcription factor 1 (ETS-1), which is involved in VEGF-A/VEGFR2 regulation. Overexpression of ETS-1 reversed the inhibitory effects of TC-G 1008 on VEGF-A/VEGFR2 levels and angiogenic tube formation, confirming the critical role of ETS-1 in this pathway. These findings demonstrate that GPR39 activation by TC-G 1008 protects against AngII-induced AAA by mitigating oxidative stress, suppressing VEGF-A/VEGFR2 signalling, and inhibiting ETS-1-mediated angiogenesis.