Pathophysiology of thoracic aortic aneurysm (TAA): is it not one uniform aorta? Role of embryologic origin

Abstract

Thoracic aortic aneurysm (TAA) is a clinically silent and potentially fatal disease whose pathophysiology is poorly understood. Application of data derived from animal models and human tissue analysis of abdominal aortic aneurysms may prove misleading given current evidence of structural and biochemical aortic heterogeneity above and below the diaphragm. Genetic predisposition is more common in TAA and includes multi-faceted syndromes such as Marfan, Loeys-Dietz, and type IV Ehlers-Danlos as well as autosomal-dominant familial patterns of inheritance. Investigation into the consequences of these known mutations has provided insight into the cell signaling cascades leading to degenerative remodeling of the aortic medial extracellular matrix (ECM) with TGF-β playing a major role. Targeted research into modifying the upstream regulation or downstream effects of the TGF-β1 pathway may provide opportunities for intervention to attenuate TAA progression.

Keywords: AAA; AT1; AngII; ECM; ERK; Extracellular matrix remodeling; MMP; Matrix metalloproteinases; TAA; TGF-β; TGF-βR1 & 2; Thoracic Aortic Aneurysm; Transforming growth factor-beta; VSMC; abdominal aortic aneurysm; angiotensin II; angiotensin receptor 1; extracellular matrix; extracellular signal-regulated kinase; matrix metalloproteinase; t-PA; thoracic aortic aneurysm; tissue plasminogen activator; transforming growth factor beta; transforming growth factor beta receptor 1 & 2; vascular smooth muscle cell.

Figure 1

Centralized role of TGF-β1 in TAA formation. Upregulated TGF-β1 signaling in the aortic medial VSMCs may be initiated through ineffective sequestration by mutated fibrillin-1, by binding to dysfunctional receptors, or through downstream activity of AngII binding to its AT1 receptor. The generation of ROS and activation of p38MAPK can augment TGF-β1 activity. VSMC synthetic productivity is modulated by miRNA 29 and may produce MMP-2, MMP-9, and collagen. When MMPs are activated by t-PA, ECM remodeling with aneurysmal dilation ensues. Dysfunctional type III collagen and disorganization of VSMCs may further compromise the integrity of the aortic media and allow TAA formation.