Transforming growth factor-beta signaling in thoracic aortic aneurysm development: a paradox in pathogenesis

Abstract

Thoracic aortic aneurysms (TAAs) are potentially devastating, and due to their asymptomatic behavior, pose a serious health risk characterized by the lack of medical treatment options and high rates of surgical morbidity and mortality. Independent of the inciting stimuli (biochemical/mechanical), TAA development proceeds by a multifactorial process influenced by both cellular and extracellular mechanisms, resulting in alterations of the structure and composition of the vascular extracellular matrix (ECM). While the role of enhanced ECM proteolysis in TAA formation remains undisputed, little attention has been focused on the upstream signaling events that drive the remodeling process. Recent evidence highlighting the dysregulation of transforming growth factor-beta (TGF-beta) signaling in ascending TAAs from Marfan syndrome patients has stimulated an interest in this intracellular signaling pathway. However, paradoxical discoveries have implicated both enhanced TGF-beta signaling and loss of function TGF-beta receptor mutations, in aneurysm formation; obfuscating a clear functional role for TGF-beta in aneurysm development. In an effort to elucidate this subject, TGF-beta signaling and its role in vascular remodeling and pathology will be reviewed, with the aim of identifying potential mechanisms of how TGF-beta signaling may contribute to the formation and progression of TAA.

Figure 1. Classical TGF-β signaling pathway

The classical profibrotic TGF-β signaling pathway is initiated upon binding of ligand to a homodimer of the type II TGF-β receptor (TGF-βRII) (1.). The type II receptor is autophosphorylated (2.), which then recruits and transphosphorylates a type I receptor (TGF-βRI) (3.). The activated type I receptor in turn phosphorylates and activates a receptor-Smad (R-Smad) (4.). The R-Smad then binds the common co-Smad (5.) and translocates to the nucleus (6.). Once in the nucleus, it binds transcriptional co-factors and forms an activated transcriptional complex capable of inducing transcription of profibrotic genes (7.).

Figure 2. Alternative TGF-β signaling mechanisms

Signaling directly mediated by the type II receptor without type I receptor function (1.), type I receptor signaling independent of Smad function (2.), R-Smad signaling independent of co-Smad interaction (3.), and R-Smad activation in response to TGF-β but in the absence of direct TGF-β receptor interaction (4.). Adapted from reviews by Derynck[76] and Moustakas.[47]

Figure 3. Mechanisms for TGF-β induced matrix degradation

TGF-β stimulates matrix degradation primarily through non-Smad-mediated pathways that may also involve Smad activation, and results in the increased expression of extracellular protease genes. (ERK1/2, extracellular regulated kinase 1 and 2; MMP, matrix metalloproteinase; PLAU/PLAT, urokinase-type plasminogen activator/tissue-type plasminogen activator).

Figure 4. Potential mechanism for enhancement TGF-β signaling in the presence of receptor mutations

The endocytosis and subsequent recycling or degradation of TGF-β receptors is an important mechanism for regulating TGF-β signaling. There are two independent endocytic pathways, regulated by accessory protein interactions that exist to regulate TGF-β signaling: A.) the clathrin-mediated pathway leading to receptor recycling, and B.) the caveolin-mediated pathway leading to proteasomal degradation of TGF-β receptors. The TGF-βRII mutations identified in several aneurysm syndromes may contribute to the enhanced TGF-β signaling by facilitating interactions with SARA, or by diminishing association with Smad7, favoring receptor recycling and resulting in prolonged activation of TGF-β signals.

Figure 5. Potential mechanism for enhancement of TGF-β signaling in the presence of non-functional receptors

Ligand-induced receptor signaling complexes that are unable to transmit signals because of mutations within the receptor kinase domain (TGF-βRII/TGF-βRI/both), may still function by seeding active signaling platforms that localize other signaling components capable of inducing downstream signaling events that contribute to aneurysm development.

Figure 6. Potential mechanism of TGF-β-induced changes in the cellular constituents of the vascular wall during aneurysm development

A. Non-aneurysmal thoracic aorta showing normal homeostatic content of medial smooth muscle cells (SMCs) and adventitial fibroblasts. B. Thoracic aorta during aneurysm formation. TGF-β-mediated SMC apoptosis leaves the adventitial fibroblast as the predominate endogenous cell type in the vascular wall. TGF-β can induce adventitial fibroblasts to differentiate into myofibroblasts, conferring SMC-like characteristics including α-smooth muscle actin expression, enhanced contractile properties, and the ability to migrate. Migrating myofibroblasts respond to TGF-β stimulation by inducing MMP production and secretion. Thus, the resulting myofibroblast population may dominate the vascular remodeling process leading to enhanced matrix degradation.