Quercetin Downregulates Cyclooxygenase‐2 Expression and HIF‐1α/VEGF Signaling‐Related Angiogenesis in a Mouse Model of Abdominal Aortic Aneurysm

Abstract

Objective. Abdominal aortic aneurysm (AAA) development has been characterized by increased expression of vascular endothelial growth factor (VEGF), which contributes to angiogenesis via cyclooxygenase-2 (COX-2). Quercetin, one of the most common and well-researched flavonoids and abundant in vegetables and fruits, has beneficial effects in inhibiting angiogenesis. This study investigated the antiangiogenic effects of quercetin on experimental aneurysms. Methods. We utilized the in vivo AAA mouse model induced by the periaortic application of CaCl2 to examine the effectiveness of quercetin in blocking angiogenesis. Quercetin was administered at 60 mg/kg once daily on the day of the AAA induction and then continued for 6 weeks. Celecoxib, a selective COX-2 inhibitor, was used as the positive control. Results. Our results demonstrated that quercetin significantly attenuated aneurysm growth in AAA mice and medial neovascularization. Accordingly, quercetin decreased the expression of proangiogenic mediators, including VEGF-A, intercellular adhesion molecule-1, vascular cell adhesion molecule 1, and vascular endothelial cadherin. Quercetin treatment also inhibited the expression of COX-2 and hypoxia-inducible factor 1α (HIF-1α). It was also found that quercetin-3-glucuronide, a major quercetin metabolite, downregulated the expression of COX-2, HIF-1α, VEGF-A, and matrix metalloproteinase activities in aortic vascular smooth muscle cells isolated from AAA mice. Conclusion. Quercetin attenuates neovascularization during AAA growth, and this effect is mediated via the inhibition of COX-2, which decreases HIF-1α/VEGF signaling-related angiogenesis.

Potential Therapeutic Targets of Quercetin, a Plant Flavonol, and Its Role in the Therapy of Various Types of Cancer through the Modulation of Various Cell Signaling Pathways

“…In several cancers models, such as prostate and breast cancer, Qu has been associated in mediating several angiogenesis pathways, including the Vascular Endothelial Growth Factor Receptor-2 mediated pathway of angiogenesis, repressing the downstream-regulatory target AkT expression; thus, restraining and restricting growth of the tumor [ 80 , 85 ].Lian Wang et al, through a mice model study, stated that Qu, as an angiogenesis inhibitor, reduces neovascularization growth, which is mediated via the inhibition of cyclooxygenase-2 (COX-2) [ 86 ]. It also decreases the expression of proangiogenic mediators, including VEGF-A, and Hypoxia-inducible factor 1-alpha; thus, preventing metastasis of cancer cells [ 87 , 88 ].…”

Through network pharmacology and molecular docking to explore the underlying mechanism of Artemisia annua L. treating in abdominal aortic aneurysm

“…Quercetin, a flavonoid with anti-inflammatory activity, was the most abundant ingredients that could act on AAA and inhibited the development of AAA in mice (Wang et al, 2012). Additionally, quercetin attenuated neovascularization during AAA growth (Wang et al, 2020) and decreased oxidative stress in AAA mouse models (WANG et al, 2014). Luteolin inhibited vascular smooth muscle cells proliferation and migration (Xu et al, 2015;Wu et al, 2018).…”

NADPH Oxidases in Aortic Aneurysms

“…Related to this study, the treatment of murine AAAs with resveratrol, a polyphenol, resulted in decreased AAA formation and elevated phox-p47 levels [ 123 ]. In separate studies, Quercetin, a polyphenol and antioxidant, also demonstrated decreased AAA formation and decreased HIF-1α and VEGF signaling in experimental AAAs [ 124 ]. These studies using Quercetin also treated with Celecoxib, a known anti-inflammatory, separately as a positive control to confirm the ability to attenuate AAA formation.…”