Endothelial Dysfunction in the Pathogenesis of Abdominal Aortic Aneurysm

Abstract

Abdominal aortic aneurysm (AAA), defined as a focal dilation of the abdominal aorta beyond 50% of its normal diameter, is a common and potentially life-threatening vascular disease. The molecular and cellular mechanisms underlying AAA pathogenesis remain unclear. Healthy endothelial cells (ECs) play a critical role in maintaining vascular homeostasis by regulating vascular tone and maintaining an anti-inflammatory, anti-thrombotic local environment. Increasing evidence indicates that endothelial dysfunction is an early pathologic event in AAA formation, contributing to both oxidative stress and inflammation in the degenerating arterial wall. Recent studies utilizing single-cell RNA sequencing revealed heterogeneous EC sub-populations, as determined by their transcriptional profiles, in aortic aneurysm tissue. This review summarizes recent findings, including clinical evidence of endothelial dysfunction in AAA, the impact of biomechanical stress on EC in AAA, the role of endothelial nitric oxide synthase (eNOS) uncoupling in AAA, and EC heterogeneity in AAA. These studies help to improve our understanding of AAA pathogenesis and ultimately may lead to the generation of EC-targeted therapeutics to treat or prevent this deadly disease.

Mechanosignals in abdominal aortic aneurysms

“…In vivo studies by Xie et al ( 32 ) showed that ECs subjected to LSS and disturbed flow undergo increased apoptosis through increased monocyte adhesion and inflammatory responses. While HSS is physiologically observed in the normal abdominal aorta, the laminar flow pattern is switched to LSS patterns exerting additional stress on the endothelium once the aortic tissue is deformed into a bulged structure, introducing new curvatures within the AAA sac ( 33 ). Observations in patients with aneurysms have demonstrated that LSS magnitude is co-incident with rupture sites ( 2 – 4 , 12 , 34 ), further emphasizing the association between LSS and the severity of AAA.…”

Towards Precritical Medical Therapy of the Abdominal Aortic Aneurysm

“…In this last cohort, it has also been shown that tea consumption, rich in catechins, up to ≥2 servings per day, was associated with a lower risk of both non-ruptured and ruptured AAA [ 16 ]. From a mechanistic point of view, diet polyphenols may potentially interfere through their antioxidant properties with many factors involved in AAA development by: reducing inflammation [ 17 ]; restoring endothelial function, [ 18 ] which is known to be altered in AAA [ 19 ]; decreasing DNA global methylation [ 20 , 21 ]; and protecting against telomere attrition [ 22 , 23 ].…”

Single-cell transcriptome in silico analysis reveals conserved regulatory programs in macrophages/monocytes of abdominal aortic aneurysm from multiple mouse models and human

“…Various inflammatory cell types in AAA, such as macrophages, CD4 + T cells, and B cells, had great importance in the pathological aortic wall through phenotypic regulation ( 7 ). In addition, continuous crosstalk between various cells also affected the occurrence and development of AAA ( 8 , 9 ). Therefore, the study of cell heterogeneity in the development of AAA may be a breakthrough to further understand its pathogenesis and develop targeted drugs.…”