Elastic fibers and biomechanics of the aorta: Insights from mouse studies

Abstract

Elastic fibers are major components of the extracellular matrix (ECM) in the aorta and support a life-long cycling of stretch and recoil. Elastic fibers are formed from mid-gestation throughout early postnatal development and the synthesis is regulated at multiple steps, including coacervation, deposition, cross-linking, and assembly of insoluble elastin onto microfibril scaffolds. To date, more than 30 molecules have been shown to associate with elastic fibers and some of them play a critical role in the formation and maintenance of elastic fibers in vivo. Because the aorta is subjected to high pressure from the left ventricle, elasticity of the aorta provides the Windkessel effect and maintains stable blood flow to distal organs throughout the cardiac cycle. Disruption of elastic fibers due to congenital defects, inflammation, or aging dramatically reduces aortic elasticity and affects overall vessel mechanics. Another important component in the aorta is the vascular smooth muscle cells (SMCs). Elastic fibers and SMCs alternate to create a highly organized medial layer within the aortic wall. The physical connections between elastic fibers and SMCs form the elastin-contractile units and maintain cytoskeletal organization and proper responses of SMCs to mechanical strain. In this review, we revisit the components of elastic fibers and their roles in elastogenesis and how a loss of each component affects biomechanics of the aorta. Finally, we discuss the significance of elastin-contractile units in the maintenance of SMC function based on knowledge obtained from mouse models of human disease.

Figure 1.. Proposed model of elastogenesis.

Tropoelastin is secreted by elastogenic cells, binds to fibulins (predominantly fibulin-5), and undergoes self-aggregation (coacervation). Fibulin-5 binds to LOXL1 and fibulin-4 binds to LOX and the complexes are deposited onto microfibrils (green) with the aid of LTBP-4S and LTBP-4L, respectively. Cross-linking and polymerization of elastic fibers proceed.

Figure 2.. Pressure-diameter curves for ascending aorta from adult mice with elastic fiber defects.

Absolute values of the outer diameter at each pressure (A) and normalized values with respect to the starting outer diameter at 0 mmHg (B) are shown. The local slope of the curve represents the structural stiffness. The black circles on each curve mark the approximate transition from low stiffness (elastin dominated) to high stiffness (collagen dominated) behavior. Aortas from mice with elastic fiber defects transition to high stiffness at lower pressures than wild-type, with aneurysmal models having the lowest transition pressure. Data was approximated from [55] for Eln^+/−, [61] for Fbln5^−/−, [65] for Fbln4^E57K/E57K, [66] for Fbln4^SMKO, [73] for Lox^+/M298R, and [78] for Fbn1^mgR/^mgR. The wild-type (WT) curve was estimated from the average behavior of three different studies[55, 61, 66].

Figure 3.. Schematic presentation of the elastin-contractile unit in SMCs.

Elastic fibers bind to α- and β- heteromeric integrins through elastin extensions and form dense plaques (orange), where focal adhesion proteins such as Talin, paxillin (Px), focal adhesion kinase (FAK) and integrin linked kinase (ILK) bind and regulate contractile filaments (red, major isoform is ACTA2) as well as activate various downstream signaling. Cellular tension is generated by the contraction of actin and myosin (pink, major isoform is MYH11). The regulators of muscle contraction such as PKG-1 and MLCK also play a crucial role in response to mechanical stimuli. The defects in elastin-contractile units result in the formation of thoracic aortic aneurysms. EL: elastic lamina.