Therapeutics Targeting Drivers of Thoracic Aortic Aneurysms and Acute Aortic Dissections: Insights from Predisposing Genes and Mouse Models

Abstract

Thoracic aortic diseases, including aneurysms and dissections of the thoracic aorta, are a major cause of morbidity and mortality. Risk factors for thoracic aortic disease include increased hemodynamic forces on the ascending aorta, typically due to poorly controlled hypertension, and heritable genetic variants. The altered genes predisposing to thoracic aortic disease either disrupt smooth muscle cell (SMC) contraction or adherence to an impaired extracellular matrix, or decrease canonical transforming growth factor beta (TGF-β) signaling. Paradoxically, TGF-β hyperactivity has been postulated to be the primary driver for the disease. More recently, it has been proposed that the response of aortic SMCs to the hemodynamic load on a structurally defective aorta is the primary driver of thoracic aortic disease, and that TGF-β overactivity in diseased aortas is a secondary, unproductive response to restore tissue function. The engineering of mouse models of inherited aortopathies has identified potential therapeutic agents to prevent thoracic aortic disease.

Keywords: ACTA2; Marfan syndrome; TGF-β; angiotensin receptor; aortopathy; losartan; mutation; phenotype; thoracic aortic disease.

Conflict of interest statement

DISCLOSURE STATEMENT

The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

Figures

Figure 1

Schematic representation of thoracic aortic aneurysms and aortic dissections.

Figure 2

Schematic representation of a cross section of the aorta illustrating the intimal layer of endothelial cells and the first three out of >50 layers of elastin lamellae and smooth muscle cells (SMCs). The elastic lamellae (black) and SMCs (pink) are connected through oblique extensions of elastin to the surface of the SMCs. The microfibrils at the end of the elastin extensions link to integrin receptors in the focal adhesions on the SMC surface. The contractile units, composed of SM α-actin (the SMC-specific isoform of α-actin) and myosin filaments, attach to the focal adhesions and extend obliquely across the cells. The direction of these oblique extensions changes from layer to layer.