Molecular mechanisms of thoracic aortic dissection

Abstract

Thoracic aortic dissection (TAD) is a highly lethal vascular disease. In many patients with TAD, the aorta progressively dilates and ultimately ruptures. Dissection formation, progression, and rupture cannot be reliably prevented pharmacologically because the molecular mechanisms of aortic wall degeneration are poorly understood. The key histopathologic feature of TAD is medial degeneration, a process characterized by smooth muscle cell depletion and extracellular matrix degradation. These structural changes have a profound impact on the functional properties of the aortic wall and can result from excessive protease-mediated destruction of the extracellular matrix, altered signaling pathways, and altered gene expression. Review of the literature reveals differences in the processes that lead to ascending versus descending and sporadic versus hereditary TAD. These differences add to the complexity of this disease. Although tremendous progress has been made in diagnosing and treating TAD, a better understanding of the molecular, cellular, and genetic mechanisms that cause this disease is necessary to developing more effective preventative and therapeutic treatment strategies.

Keywords: Aneurysm; Aortic dissection; Degeneration; Media.

Fig 1

Key structural components of the aorta. The media of the aortic wall is composed of vascular smooth muscle cells (SMCs) and an extracellular matrix (ECM) of elastic fibers, collagen fibers, and proteoglycans. Elastic fiber is the major ECM component and provides extensibility to the aortic wall. Cross-linking of tropoelastin monomers by lysyl oxidase (LOX) forms elastin molecules, which in turn cross-link with microfibrils to form elastic fibers. Microfibrils provide a scaffold for tropoelastin cross-linking. Microfibrils are composed of fibrillin and several microfibril-associated proteins (MFAPs), such as elastin microfibril interface-located protein 1 (EMILIN-1), microfibril-associated glycoproteins (MAGP-1 and -2), and fibulins.

Fig 2

Aortic inflammation. Injured or stressed SMCs produce chemokines such as monocyte chemoattractant protein 1 (MCP-1) to promote the recruitment of inflammatory cells to the aortic wall. Elastin fragments are also strong monocyte chemoattractants. Extracellular matrix proteases such as MMPs (matrix metalloproteinase) and ADAMTS (A disintegrin and metalloproteinase with thrombospondin motifs) produced from SMCs and macrophages are capable of directly degrading the elastic fibers and proteoglycan, respectively. The ECM degradation contributes to the SMC detachment from the ECM. Inflammation also causes SMC injury, dedifferentiation, dysfunction, and, ultimately, death.

Fig 3

TGF-β signaling. TGF-β binds and activates its receptor (TGFBR). In the canonical pathway, the active complex proceeds to phosphorylate Smad 2 and Smad 3 proteins, which recruit Smad 4 to form a Smad2/3-Smad4 complex. This complex translocates to the nucleus, activating the transcription of TGF-β target genes that affect cell proliferation, cell death, and extracellular matrix (ECM) destruction. TGF-β signaling can be antagonized at the receptor level by Smad 7. The proto-oncoproteins Ski and SnoN also negatively regulate the TGF-β signaling by directly interacting with the Smad2/3-Smad4 complex.