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.

Keywords: abdominal aortic aneurysm; endothelial cell; endothelial cell heterogeneity; endothelial nitric oxide synthase.

Figure 1

Diagram depicting mechanisms by which endothelial dysfunction contributes to AAA growth, including eNOS uncoupling, a phenotypic switch to a pro-thrombotic, pro-adhesive, permeable state in the setting of altered biomechanical stress, and EC stress generated by intraluminal thrombus accumulation. EC populations 1 and 2 as determined by single-cell RNA sequencing are shown in distinct colors (pink, purple) in low (light) and high (dark) stress states. Potential biomarkers (circulating TM, CCL2, EPCs, and FMD analysis) are depicted. Tobacco use is highlighted as a clinical risk factor for endothelial dysfunction and AAA progression. Abbreviations: AAA (abdominal aortic aneurysm); ARG (arginine); CCL20 (C-C Motif Chemokine Ligand 20); CIT (citrulline); EC (endothelial cell); eNOS (endothelial nitric oxide synthase); EPC (endothelial progenitor cell); FMD (flow mediated dilation); MMP (matrix metalloproteinase); NO (nitric oxide); TM (thrombomodulin).