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 over-activity 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.

Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease

“…In some studies, surgery for TAD, postmortem examination, or sudden death were used to assess the aortic phenotype. Molecular genetic testing approaches included a combination of gene‐targeted testing (multigene panel or single gene testing) and whole exome of genome sequencing 16, 17, 18…”

Systems pharmacology–based integration of human and mouse data for drug repurposing to treat thoracic aneurysms

“…Thoracic aortic aneurysms (TAAs) are life-threatening pathologies characterized by progressive vessel dilation associated with smooth muscle cell (SMC) dysfunction, occasional localized inflammatory infiltrates, and severe maladaptive extracellular matrix (ECM) remodeling that, together, predispose the arterial wall to dissection and rupture leading to premature death (4). Consistent with the progressively degenerative nature Marfan syndrome (MFS) is associated with mutations in fibrillin-1 that predispose afflicted individuals to progressive thoracic aortic aneurysm (TAA) leading to dissection and rupture of the vessel wall.…”

“…of the disease, inherited forms of TAA are accounted for by mutations in molecules involved in supporting tissue integrity and homeostasis, such as components of the ECM, SMC contractile apparatus and its mediators, and TGF-β signaling pathways (4). Yet, the molecular mechanisms and SCPs that translate these different genetic defects into a seemingly identical pathology are not fully understood.…”

“…TAA with ensuing dissection and rupture of the vessel wall is the clinical hallmark of Marfan syndrome (MFS), a relatively common connective tissue disease associated with mutations in the gene that codes for the multifunctional ECM glycoprotein fibrillin-1 (4,5). Fibrillin-1 assemblies (microfibrils and elastic fibers) impart specific physical properties to tissues, distribute mechanical forces within and across them, communicate to multiple types of vessel wall cells through integrin receptors, and modulate local bioavailability of ECM-bound latent TGF-β complexes (5).…”

Anatomically specific reactive oxygen species production participates in Marfan syndrome aneurysm formation

“…The specific role TGF-β plays during aneurysm formation in MFS murine models remains complicated, although most animal studies support a pathologic function through aortic wall remodelling in two different Marfan mouse models (Fbn1 mgR/mgR and Fbn1 C1039G/+ ). [5][6][7][8][9][10][11][12][13][14]32,33 Identifying key components within the molecular pathway(s) that lead to aneurysm formation may translate into innovative medical therapies directed at preventing or slowing aneurysm growth 33,34 . Herein, our laboratory reports that ROS contribute to aneurysm formation in MFS.…”