Structure of the Elastin-Contractile Units in the Thoracic Aorta and How Genes That Cause Thoracic Aortic Aneurysms and Dissections Disrupt This Structure

Abstract

The medial layer of the aorta confers elasticity and strength to the aortic wall and is composed of alternating layers of smooth muscle cells (SMCs) and elastic fibres. The SMC elastin-contractile unit is a structural unit that links the elastin fibres to the SMCs and is characterized by the following: (1) layers of elastin fibres that are surrounded by microfibrils; (2) microfibrils that bind to the integrin receptors in focal adhesions on the cell surface of the SMCs; and (3) SMC contractile filaments that are linked to the focal adhesions on the inner side of the membrane. The genes that are altered to cause thoracic aortic aneurysms and aortic dissections encode proteins involved in the structure or function of the SMC elastin-contractile unit. Included in this gene list are the genes encoding protein that are structural components of elastin fibres and microfibrils, FBN1, MFAP5, ELN, and FBLN4. Also included are genes that encode structural proteins in the SMC contractile unit, including ACTA2, which encodes SMC-specific α-actin and MYH11, which encodes SMC-specific myosin heavy chain, along with MYLK and PRKG1, which encode kinases that control SMC contraction. Finally, mutations in the gene encoding the protein linking integrin receptors to the contractile filaments, FLNA, also predispose to thoracic aortic disease. Thus, these data suggest that functional SMC elastin-contractile units are important for maintaining the structural integrity of the aorta.

Figure 1

Schematic representations of cross sections of the aorta demonstrating the relationship between the elastin lamellae and the smooth muscle cells (SMCs). A. The elastic lamellae are depicted as the black layers and the SMCs are shown between elastic lamellae. The elastin has oblique extensions that connect with the surface of the SMCs at focal adhesions (also called dense plaques). The SM α-actin filaments attach to the membrane at these focal adhesions and extend obliquely across the cell. The direction of these oblique extensions changes from layer to layer. B. The SMCs are shown in cross section between the elastin lamellae. The elastin extensions to the SMCs are viewed in cross-section at the edge of the elastic lamellae and give the elastin fibers an irregular appearance. Reproduced with permission from Davis EC et al.

Figure 2

The elastin-contractile unit in smooth muscle cells. The altered genes that predispose to thoracic aortic aneurysms and acute aortic dissections are indicated. The location of the gene indicates where its protein product is located in the elastin-contractile unit.