Abstract
Transforming growth factor-β (TGF)-β signaling plays a crucial role in the development and maintenance of various organs, including the vasculature. Accordingly, the mutations in TGF-β signaling pathway-related genes cause heritable disorders of the connective tissue, such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS), and these syndromes may affect skeletal, ocular, pulmonary, and cardiovascular systems. Aortic root aneurysms are common problems that can result in aortic dissection or rupture, which is the leading cause of sudden death in the natural history of MFS and LDS, and recent improvements in surgical treatment have improved life expectancy. However, there is currently no genotype-specific medical treatment. Accumulating evidence suggest that not only structural weakness of connective tissue but also increased TGF-β signaling contributes to the complicated pathogenesis of aortic aneurysm formation, but a comprehensive understanding of governing molecular mechanisms remains lacking. Inhibition of angiotensin II receptor signaling and endothelial dysfunction have gained attention as a possible MFS treatment strategy, but interactions with TGF-β signaling remain elusive. Heterozygous loss-of-function mutations in TGF-β receptors 1 and 2 (TGFBR1 and TGFBR2) cause LDS, but TGF-β signaling is activated in the aorta (referred to as the TGF-β paradox) by mechanisms yet to be elucidated. In this review, we present and discuss the current understanding of molecular mechanisms responsible for aortopathies of MFS and related disorders.
Highlights
Thoracic aortic aneurysms (TAAs) increase the risk of aortic dissection or rupture, and inherited forms of thoracic aortic aneurysms and dissections (TAADs) can be fatal early in life if patients do not receive appropriate care
Expression of smooth muscle cells (SMCs) differentiation markers, such as αSMA, SM22α, and smoothelin, decrease in the medial layer [7], and inflammatory T lymphocytes and macrophages infiltrate aortic media and adventitia [8,9]. These data suggest that active signals contribute to the formation of the aortic aneurysm, and molecular mechanisms have been actively investigated since the causative fibrillin-1 (FBN1) gene at chromosome 15q21 was identified by Harry Dietz and colleagues in 1991 [10]
Genetic tests enabled the definite and rapid diagnosis, which might be useful for detection of high-risk subgroups requiring rapid surgical intervention, such as Marfan syndrome (MFS) patients with HI-type mutations and Loeys-Dietz syndrome (LDS) patients
Summary
Thoracic aortic aneurysms (TAAs) increase the risk of aortic dissection or rupture, and inherited forms of thoracic aortic aneurysms and dissections (TAADs) can be fatal early in life if patients do not receive appropriate care. Familial TAAD can be divided into two broad categories: syndromic (associated with abnormalities of other organ systems) and non-syndromic (with manifestations restricted to the aorta) [1,2]. Mutations in transforming growth factor-β (TGF-β) signaling pathway-related genes cause syndromic TAAD, such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS), and these syndromes potentially affect skeletal, ocular, pulmonary, and cardiovascular systems [3,4]. Acute aortic dissection is the leading cause of sudden death in the natural history of MFS and LDS [5], and improved surgical management has increased life expectancy; comprehensive understanding of molecular mechanisms governing multiple aortic aneurysms and dissections remains unclear. We present and discuss current molecular knowledge of aortopathies caused by mutations in TGF-β signaling-related genes and related aortopathy models
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