TGF-β Signaling-Related Genes and Thoracic Aortic Aneurysms and Dissections

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.

Endothelial TGF-β signaling instructs smooth muscle development in the cardiac outflow tract

“…The TGF-β pathway’s multi-functional role results in many context- and tissue-dependent functions, which are difficult to unravel (Pardali et al, 2010). Most studies on diseases of the great arteries have aimed to understand the role of TGF-β in SMCs (Li et al, 2014; Yang et al, 2016; Zhang et al, 2016; Perrucci et al, 2017; Takeda et al, 2018), overlooking its function in the endothelium. In EC biology, Alk5 function has been mostly studied in vitro , where it has been shown to maintain EC quiescence (Goumans et al, 2002; Goumans et al, 2003; Lebrin et al, 2004; van Meeteren and ten Dijke, 2012; Maring et al, 2016).…”

“…Multiple signaling pathways including BMP, Notch, FGF, Wnt, and TGF-β have been implicated in OFT development (Neeb et al, 2013). In particular, mutations in several of the TGF-β family members have been associated with severe congenital heart diseases, such as PTA and aneurysm of the great vessels (Todorovic et al, 2007; Gillis et al, 2013; Takeda et al, 2018). Despite the clear importance of the TGF-β signaling pathway in the development and homeostasis of the OFT and connecting vessels, the molecular mechanisms underlying these defects remain elusive, due to the context-dependent and controversial role of this pathway (Massague, 2012; Cunha et al, 2017; Goumans and Ten Dijke, 2018; Zhang, 2018).…”

“…Despite the evidence for a potential role for ALK5 in the endothelium, most studies in OFT and aortic pathologies, such as aortic aneurysms, have been focused on the role of TGF-β signaling in SMCs and not ECs (Choudhary et al, 2009; Guo and Chen, 2012; Gillis et al, 2013; Yang et al, 2016; Takeda et al, 2018). In particular, aneurysms have been described as a weakening of the aortic wall due to SMC-specific defects, resulting in the dissection of the vessel (Takeda et al, 2018). Only recently have a few studies started considering the endothelium as a potential therapeutic target in OFT and aortic pathologies (van de Pol et al, 2017; Sun et al, 2018).…”

The genetics and biomechanics of thoracic aortic diseases

“…Sources demonstrate TGFB as a significant molecule involved in the hallmark features of TAAD, particularly in those with MFS and LDS (84,87). For example, TGFB1 is thought to promote TAAD development and is found elevated in human and animals with aortic aneurysm (88).…”

Unique Mechanism by Which <i>TGFBR1</i> Variants Cause 2 Distinct System Diseases ― Loeys-Dietz Syndrome and Multiple Self-Healing Squamous Epithelioma ―

“…14 There has been speculation that increased TGF-β ligands in the LDS aortic wall activate intact TGFBR1/ TGFBR2 complexes in vivo ( Figure 1C), but the mechanisms of how TGF-β ligands are actively secreted remain to be determined. 15 In this mini review, we present and discuss the recent understanding of the molecular mechanism of LDS and the unresolved problems, including the TGF-β signaling paradox and the mechanism by which TGFBR1 variants elicit 2 completely distinct diseases, LDS and MSSE. 7…”