Elastin, arterial mechanics, and cardiovascular disease

Abstract

Large, elastic arteries are composed of cells and a specialized extracellular matrix that provides reversible elasticity and strength. Elastin is the matrix protein responsible for this reversible elasticity that reduces the workload on the heart and dampens pulsatile flow in distal arteries. Here, we summarize the elastin protein biochemistry, self-association behavior, cross-linking process, and multistep elastic fiber assembly that provide large arteries with their unique mechanical properties. We present measures of passive arterial mechanics that depend on elastic fiber amounts and integrity such as the Windkessel effect, structural and material stiffness, and energy storage. We discuss supravalvular aortic stenosis and autosomal dominant cutis laxa-1, which are genetic disorders caused by mutations in the elastin gene. We present mouse models of supravalvular aortic stenosis, autosomal dominant cutis laxa-1, and graded elastin amounts that have been invaluable for understanding the role of elastin in arterial mechanics and cardiovascular disease. We summarize acquired diseases associated with elastic fiber defects, including hypertension and arterial stiffness, diabetes, obesity, atherosclerosis, calcification, and aneurysms and dissections. We mention animal models that have helped delineate the role of elastic fiber defects in these acquired diseases. We briefly summarize challenges and recent advances in generating functional elastic fibers in tissue-engineered arteries. We conclude with suggestions for future research and opportunities for therapeutic intervention in genetic and acquired elastinopathies.

Keywords: aorta; compliance; elasticity; extracellular matrix; stiffness.

Fig. 1.

Domain structure of the human elastin gene. Alternating hydrophobic and cross-linking domains are generally transcribed by individual exons. The locations of 64 unique polymorphisms (Human Gene Mutation Database, www.hgmd.cf.ac.uk) associated with either supravalvular aortic stenosis (SVAS; red, 49 mutations not including large deletions) or autosomal dominant cutis laxa-1 (ADCL1; blue, 15 mutations) are indicated.

Fig. 2.

Structure of the elastin network in arterial elastic laminae. En face images of elastin in a wild-type mouse ascending aorta obtained using nonlinear fluorescence microscopy are shown (166). A dense, fenestrated (arrows) elastin network can be observed in elastic laminae near the inner media (left). The network appears more fibrous toward the outer media (right). Circumferential direction is horizontal; axial direction is vertical. Scale bars = 20 μm.

Fig. 3.

Organization of the elastic laminae in large and small arteries. Cross-sections of a mouse descending aorta (A) and mesenteric artery (B) stained for elastin (red) and cell nuclei (blue) are shown (93). The descending aorta has multiple layers of elastic laminae. The mesenteric artery has an internal elastic lamina at the luminal surface and a thin external elastic lamina at the adventitial surface. L, lumen. Scale bars = 20 μm.

Fig. 4.

Effects of elastin amounts on arterial mechanical behavior. A−D: representative pressure-outer diameter (A and B) and circumferential Cauchy stress-stretch ratio (C and D) curves (197) for the ascending aorta (ASC; A and C) and left common carotid (LCC; B and D) from wild-type (WT; 100% elastin), Eln^+/− (50–60% elastin), and hBAC-mNull (30–40% elastin) mice. Decreased elastin amounts shift the pressure-diameter behavior for both artery locations, but the difference between Eln^+/− and hBAC-mNull pressure-diameter behavior for the LCC is negligible. For both artery locations, the stress-stretch behavior is similar between WT and Eln^+/− mice but becomes more nonlinear at lower stretch ratios for hBAC-mNull mice. The data highlight the importance of examining structural (pressure-diameter) and material (stress-stretch) mechanical behavior as well as differences between artery locations in the structural response to reduced elastin amounts. The results suggest that mouse arteries can remodel to maintain WT material behavior when elastin amounts are 50–60% of normal but cannot fully remodel and adapt the material behavior when elastin amounts are 30–40% of normal.

Fig. 5.

Effects of elastin amounts on arterial wall structure and composition. A−I: Histological sections (93) of the left common carotid artery from wild-type (WT) mice with 100% elastin (A, D, and G), Eln^+/− mice with 50–60% elastin (B, E, and H), and hBAC-mNull mice with 30–40% elastin (C, F, and I). A–C: Verhoeff-Van Gieson (VVG)-stained sections show black elastic laminae, brown muscle tissue, and pink collagen. The elastic laminae are thinner, more numerous, and have more diffuse staining as elastin amounts decrease. D−F: picrosirius red (PSR)-stained sections show collagen fibers in red and other material in yellow. In WT arteries, red collagen clearly outlines the yellow elastic laminae. In Eln^+/− and hBAC-mNull arteries, the collagen staining overlaps with the elastic laminae. G−I: hematoxylin and eosin (H&E)-stained sections show cell nuclei in purple and other material in pink. Scale bars = 20 μm.

Fig. 6.

Effects of elastin amounts on arterial morphology. Yellow latex (172) was injected for contrast into the ascending aorta, major branches, and descending thoracic aorta in wild-type (WT; 100% elastin), Eln^+/− (50–60% elastin), and hBAC-mNull (30–40% elastin) mice. With decreasing elastin amounts, the aortic diameter decreases and length increases. There are also changes in branching morphology with reduced elastin amounts. Scale bars = 1 mm.

Fig. 7.

Effects of elastin amounts on medial calcification caused by matrix Gla protein (MGP) deficiency. Mgp^−/− mouse arteries show extensive mineral deposition (black) along the elastic laminae (A), which is markedly reduced (arrows) in Mgp^−/−Eln^+/− mice (B). Thin plastic sections of the thoracic aortae from 2-wk-old mice were stained with von Kossa and van Gieson (79). Scale bars = 20 μm.