Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Abstract

Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin–myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease.

A Novel Human Biospecimen Repository for Clinical and Molecular Investigation of Thoracic Aortopathy

“…There are approximately 30 genes associated with TAA and dissection, and 11 of these genes were designated as definitive causes [ 13 ]. Understanding the biological roles for these genes and development of mouse models has increased the understanding of cellular and molecular mechanisms in heritable TAA [ 4 ]. Genotype–phenotype correlations have been developed over time, some of which have been adopted in clinical practice guidelines [ 14 ].…”

“…In addition, bicuspid aortic valve (BAV) is the most common form of congenital heart disease and is frequently associated with TAA. Components of TAA pathogenesis have been elucidated from human genetics discoveries and mouse models [ 4 ]. Over time, molecular testing has begun facilitating organized approaches to prognosis and clinical decision making.…”

Case Report: Occurrence of Severe Thoracic Aortic Aneurysms (Involving the Ascending, Arch, and Descending Segments) as a Result of Fibulin-4 Deficiency: A Rare Pathology With Successful Management

“…While a hereditary predisposition to TAA very strongly increases the risk of aortopathy to all segments of the vessel, pathogenic mechanisms can vary depending on the specific aortic location ( 5 ). Mutations that cause TAA interfere with the function of genes that encode components of the extracellular matrix (ECM) or proteins implicated in the transduction of either mechanical or biochemical signals in vascular smooth muscle cells ( 5 ).…”

“…While a hereditary predisposition to TAA very strongly increases the risk of aortopathy to all segments of the vessel, pathogenic mechanisms can vary depending on the specific aortic location ( 5 ). Mutations that cause TAA interfere with the function of genes that encode components of the extracellular matrix (ECM) or proteins implicated in the transduction of either mechanical or biochemical signals in vascular smooth muscle cells ( 5 ). The major spectrum of heritable connective tissue diseases related to aortopathy tend to follow an autosomal dominant pattern of inheritance but some mutations (such as those in the EFEMP2 gene, alias FBLN4 ) that result in aneurysms are autosomal recessive in nature ( 6 ).…”

“…EFEMP2 encodes an ECM protein fibulin-4, which is involved in the elastic fiber assembly and function and is related to smooth muscle cell differentiation and aortic contractility ( 7 ). Mutations in EFEMP2 are associated with the disease phenotype autosomal recessive cutis laxa type 1B (ARCL 1B, MIM number: 614437) ( 5 ). ARCL 1B is extremely rare, results in high lethality in early childhood and can be complicated by aortic aneurysm and vascular tortuosity in addition to cutis laxa ( 8 ).…”