Bouncing Back From Elastin Deficiency

Abstract

Large arteries are comprised of vascular smooth muscle cells (SMCs) embedded within a complex, cell-derived extracellular matrix. Collagen and elastic fibers, the major constituents of the vascular matrix, are secreted and assembled by SMCs and confer tensile and elastic properties. In the medial layer of elastic arteries, elastin forms concentric fenestrated lamellar layers that intercalate with alternating rings of SMCs to form functional lamellar units. 1 In the aorta, elastic fibers represent the largest component of the extracellular matrix, contributing up to 50% of aortic dry weight. 2 A series of elegant reports has demonstrated a critical role for elastin in the regulation of vascular morphogenesis in mice. Elastin (eln)-null mice die shortly after birth because of aortic obstruction by SMC proliferation. 3 Heterozygous mice (eln / ) are viable but produce 50% less elastin mRNA and protein these animals are hypertensive, exhibit thinner elastic lamellae, more lamellar units, decreased aortic compliance, and mild cardiac hypertrophy compared with eln / mice. 4 Extensive experimental studies have revealed that elevated arterial pressure is an adaptation to maintain cardiac output and tissue perfusion in spite of vessel stiffness,5 whereas the increase in lamellar unit number is an adaptation to normalize wall stress.6 In this issue of Circulation Research, Hirano et al report the phenotypic rescue of elastin-deficient mice by generation of a humanized elastin mouse. 7 Using a bacterial artificial chromosome encoding the entire human elastin gene (hBAC), they engineered mice to express functional human elastin (ELN) under the control of its native promoter. Several transgenic founder lines demonstrated at least 1 functional ELN insert and were capable of producing human elastin mRNA. Spatial and temporal expression of the human ELN transgene was similar to endogenous mouse elastin. Moreover, the hBAC mRNA product was appropriately spliced, and the protein was correctly secreted, assembled, and incorporated into mouse elastic fibers. At first glance, it may seem surprising that human elastin can substitute for mouse elastin, considering the differences in exon splicing and the lower than average amino acid conservation between species. In retrospect, however, Hirano et al might have expected the 2 proteins to be interchangeable, because it is primarily the structure of the elastin protein that is important for function. The alternating hydrophobic and crosslinking domains of elastin are conserved throughout vertebrate evolution, 8 and it is this repetitive domain structure that promotes the self-assembly of elastin into fibrillar structures,9 provides elastomeric properties,10,11 and stabilizes elastin to withstand repeated cycles of extension and recoil. 12 Transgenic expression of human elastin prevented lethality in the eln-null mouse, although the rescued animals expressed only 30% of normal elastin levels. In accordance with the lower elastin content, these animals exhibited a more severe cardiovascular phenotype than eln / mice, evidenced by stiffer vessels, higher blood pressure, and greater cardiac hypertrophy. Introduction of the hBAC into the eln / mice increased elastin content by 40%, and this resulted in a decrease in lamellar unit number and arterial pressure to levels measured in eln / mice, and partially restored vascular compliance. Taken together, these findings suggest a direct relationship between the amount of elastin produced (mouse and human combined) and the severity of the cardiovascular defect in mice. Thus, these mice might provide an elegant system for teasing apart the different thresholds for elastin expression which lead to specific abnormalities in elastic tissues. Indeed, these authors have also used this model to investigate elastin-dosing effects on lung development and susceptibility to smoke-induced emphysema.13