Aortic aneurysms: current pathogenesis and therapeutic targets

Abstract

Aortic aneurysm is a chronic disease characterized by localized expansion of the aorta, including the ascending aorta, arch, descending aorta, and abdominal aorta. Although aortic aneurysms are generally asymptomatic, they can threaten human health by sudden death due to aortic rupture. Aortic aneurysms are estimated to lead to 150,000 ~ 200,000 deaths per year worldwide. Currently, there are no effective drugs to prevent the growth or rupture of aortic aneurysms; surgical repair or endovascular repair is the only option for treating this condition. The pathogenic mechanisms and therapeutic targets for aortic aneurysms have been examined over the past decade; however, there are unknown pathogenic mechanisms involved in cellular heterogeneity and plasticity, the complexity of the transforming growth factor-β signaling pathway, inflammation, cell death, intramural neovascularization, and intercellular communication. This review summarizes the latest research findings and current pathogenic mechanisms of aortic aneurysms, which may enhance our understanding of aortic aneurysms.

Fig. 1. Pathogenesis of aortic aneurysms.

Schematic diagrams showing events that contribute to the development and progression of aortic aneurysms from the healthy to the ruptured state. Aortic aneurysmal lesions are characterized by inflammatory cell infiltration, cytokine production, matrix metalloproteinase (MMP) activation, extracellular matrix (ECM) degradation, smooth muscle cell (SMC) phenotypic switching, SMC death, neovascularization, and thrombosis.

Fig. 2. Different consequences of neutralizing TGF-β in mouse aortic aneurysm models.

Neutralizing transforming growth factor-β (TGF-β) in mouse aortic aneurysm models results in different effects on the progression of aortic aneurysms depending on the experimental design, including antibody dose, number and timing of the injections, and genetic background. Ang II angiotensin II, ApoE apolipoprotein E, SMC smooth muscle cell.

Fig. 3. Intramural thrombosis and neovascularization in aortic aneurysm.

Thrombus-mediated deprivation of oxygen and nutrients in the aortic wall stimulates neovascularization from the vasa vasorum in the aneurysm wall, inducing the recruitment of inflammatory cells that produce inflammatory mediators and leading to the weakening of the aneurysm wall and aneurysm rupture. RBC red blood cell, MMPs matrix metalloproteinases, ECM extracellular matrix.

Fig. 4. Intercellular communication by extracellular vesicles in aortic aneurysm.

Extracellular vesicles (EVs) contain various contents with biological activity, including proinflammatory and anti-inflammatory cytokines, nucleic acids, enzymes, and proteins. EVs are released from donor cells to the bloodstream and are delivered to target cells or organs. Depending on the cargo in EVs, EVs can promote or prevent the progression of aortic aneurysms. MSC mesenchymal stem cell, ADSC adipose-derived mesenchymal stem cell, ECM extracellular matrix, MMPs matrix metalloproteinases, SMC smooth muscle cell, ROS reactive oxygen species.