Crossing Bridges between Extra- and Intra-Cellular Events in Thoracic Aortic Aneurysms

Abstract

Thoracic aortic aneurysms (TAAs) are common, life-threatening diseases and are a major cause of mortality and morbidity. Over the past decade, genetic approaches have revealed that 1) activation of the transforming growth factor beta (TGF-β) signaling, 2) alterations in the contractile apparatus of vascular smooth muscle cells (SMCs), and 3) defects in the extracellular matrix (ECM) were responsible for development of TAAs. Most recently, a fourth mechanism has been proposed in that dysfunction of mechanosensing in the aortic wall in response to hemodynamic stress may be a key driver of TAAs. Interestingly, the elastin-contractile unit, which is an anatomical and functional unit connecting extracellular elastic laminae to the intracellular SMC contractile filaments, via cell surface receptors, has been shown to play a critical role in the mechanosensing of SMCs, and many genes identified in TAAs encode for proteins along this continuum. However, it is still debated whether these four pathways converge into a common pathway. Currently, an effective therapeutic strategy based on the underlying mechanism of each type of TAAs has not been established. In this review, we will update the present knowledge on the molecular mechanism of TAAs with a focus on the signaling pathways potentially involved in the initiation of TAAs. Finally, we will evaluate current therapeutic strategies for TAAs and propose new directions for future treatment of TAAs.

Keywords: Elastin-contractile unit; Extracellular matrix (ECM); Mechanosensing of SMCs; Signaling pathways; TGF-β; Thoracic Aortic Aneurysm (TAA).

Fig. 1.

Structure of the aortic wall and hemodynamic stresses. The aortic wall consists of three layers: intima, media and adventitia. These layers include endothelial cells (ECs), smooth muscle cells (SMCs) and elastic laminae, and fibroblasts, respectively. One risk factor for TAAs is dysfunctional mechanosensing of SMCs in the aortic wall, which leads to increased hemodynamic stress.

Fig. 2.

Elastin-contractile unit. Electron microscopy images from CTRL and Fbln4^SMKO (SMKO) ascending aortas at P90. Elastic laminae (EL)-SMC connections are well formed in CTRL aortas (white arrows), whereas the elastic laminae are disrupted and not connected to SMCs in SMKO aorta. Scale bars = 1 µm. Figure from Yamashiro et al, “Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice” Sci. Signal. 20 Oct 2015: vol. 8, Issue 399, pp. ra105 DOI: 10.1126/scisignal.aab3141. Reprinted with permission from AAAS.

Fig. 3.

Molecular signaling pathways involved in TAA formation. The ECM protein fibulin-4 regulates lysyl oxidase (LOX) activity, which plays an important role in elastic fiber assembly. Fibrillin-1 is a major component of extracellular microfibrils. Inactive TGF-β is tethered onto microfibrils via latent TGF-β binding proteins (LTBPs). Once TGF-β is activated by one of its activators, such as MMPs, TSPs, ROS or integrin αvβ6, it is released from latency-associated protein (LAP) and binds to its receptor (TGFBR), thus activating subsequent signaling pathways. Angiotensin II type 1 receptor (AT1R) and nitric oxide (NO) signaling pathways are involved in SMC contraction or relaxation. Integrins leads to an altered mechanotransduction signal and initiation of cellular responses such as cytoskeletal remodeling. LLC (large latent complex), SLC (small latent complex), FAK (focal adhesion kinase), ILK (integrin-linked kinase), RhoGEF (Rho guanine nucleotide exchange factor), RhoGAP (Rho GTPase-activating protein), ROCK (Rho associated kinase), MLCP (myosin light chain phosphatese), MLCK (myosin light chain kinase), PKG1 (protein kinase G 1), cGC (soluble guanylate cyclase), cGMP (cyclic guanosine monophosphate), MRTF-A (myocardin-related transcription factor A), SRF (serum response factor), JNK (c-Jun NH2-terminal kinase), ERK (extracellular signal regulated kinase), LIMK (LIM kinase), Ssh1 (slingshot-1).