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

• Published in: Journal of biochemical and molecular toxicology Vol. 39; no. 1; pp. e70118 - n/a
• Main Authors: Lei, Chenggang, Zhou, Qian, Lv, Lizhen, Liu, Di, Qian, Haiyun
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2025
• Subjects: abdominal aortic aneurysm (AAA); Angiogenesis; Angiotensin; Angiotensin II; Animals; Aorta; Aortic Aneurysm, Abdominal - chemically induced; Aortic Aneurysm, Abdominal - genetics; Aortic Aneurysm, Abdominal - metabolism; Aortic Aneurysm, Abdominal - pathology; Aortic Aneurysm, Abdominal - prevention & control; Aortic aneurysms; Apolipoprotein E; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Cardiovascular diseases; Deletion; Elastin; Endothelial cells; endothelial dysfunction; GPR4; Growth factors; Heart diseases; Humans; Inflammatory response; Interleukin 6; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Knockout, ApoE; Proteins; Receptors; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Signal Transduction; Therapeutic targets; Transcription activation; Tumor necrosis factor-TNF; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular endothelial growth factor receptor 2; VEGF; GPR4; abdominal aortic aneurysm (AAA); endothelial dysfunction; VEGF; angiogenesis
• ISSN: 1095-6670; 1099-0461; 1099-0461
• DOI: 10.1002/jbt.70118

ABSTRACT 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. This study demonstrates that GPR4 expression is significantly up‐regulated in human abdominal aortic aneurysm (AAA) tissues and in Ang II‐induced AAA mouse models. Knockout of GPR4 in ApoE−/− mice effectively reduces the incidence and severity of Ang II‐induced AAA, suggesting a protective role against aneurysm development. Mechanistically, GPR4 knockout leads to decreased expression of pro‐angiogenic factors VEGF‐A and VEGF‐R2 in abdominal artery segments and ameliorates Ang II‐induced angiogenic tube formation in human aortic endothelial cells (HAECs). These effects are mediated by the suppression of the transcription factor SP‐1, highlighting its critical role in GPR4‐related pathological pathways.