Inhibition of GPR4 Attenuates the Formation of Abdominal Aortic Aneurysm Through Inhibiting the SP-1/VEGF-A Signaling

Abdominal aortic aneurysm (AAA) is a severe cardiovascular disease (CVD) that is partly attributable to endothelial dysfunction, inflammatory response, and angiogenesis.

G protein-coupled receptor 4 (GPR4), a proton-sensitive G protein-coupled receptor that is abundantly expressed in vascular endothelial cells, has been associated with numerous physiological functions. Nevertheless, its potential involvement in the development of AAA remains unexplored.

In this study, we examined the impact of GPR4 deletion on the development of AAA in ApoE-deficient mice. The mice were categorized into four distinct groups: the ApoE−/− with saline group, the ApoE−/−GPR4−/− with saline group, the ApoE−/− with Ang II group, and the ApoE−/−GPR4−/− with Ang II group. AAA were induced in the ApoE−/− mice through the perfusion of angiotensin II (Ang II). Notably, GPR4 was substantially elevated in the AAA tissues from both human subjects and experimental mice. The deletion of GPR4 substantially decreased the formation of Ang II-induced AAA, damages to elastin, and the expression of aortic inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), as well as vascular endothelial growth factor A/vascular endothelial growth factor receptor 2 (VEGF-A/VEGF-R2), in ApoE−/− mice. Human aortic endothelial cells (HAECs) were transfected with lenti-viral GPR4 shRNA and subsequently stimulated with Ang II. Our findings indicate that the knockout of GPR4 attenuated Ang II-induced angiogenic tube formation in HAECs by decreasing the expression of VEGF-A and VEGF-R2. Furthermore, GPR4 knockout also hindered the activation of specificity protein-1 (SP-1) by reducing its expression and transcriptional activity. Notably, the overexpression of SP-1 reversed the inhibitory effects of GPR4 knockout on angiogenic tube formation and the expression of VEGF-A/VEGF-R2. This suggests that the protective effects of GPR4 knockout are achieved through the inhibition of SP-1. In summary, the absence of GPR4 impeded AAA formation, indicating that GPR4 could potentially serve as a therapeutic target for AAA.