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Elastin is an essential determinant of arterial morphogenesis

Abstract

Elastin, the main component of the extracellular matrix of arteries, was thought to have a purely structural role1. Disruption of elastin was believed to lead to dissection of arteries2,3, but we showed that mutations in one allele encoding elastin cause a human disease in which arteries are blocked, namely, supravalvular aortic stenosis4,5. Here we define the role of elastin in arterial development and disease by generating mice that lack elastin. These mice die of an obstructive arterial disease, which results from subendothelial cell proliferation and reorganization of smooth muscle. These cellular changes are similar to those seen in atherosclerosis. However, lack of elastin is not associated with endothelial damage, thrombosis or inflammation, which occur in models of atherosclerosis. Haemodynamic stress is not associated with arterial obstruction in these mice either, as the disease still occurred in arteries that were isolated in organ culture and therefore not subject to haemodynamic stress. Disruption of elastin is enough to induce subendothelial proliferation of smooth muscle and may contribute to obstructive arterial disease. Thus, elastin has an unanticipated regulatory function during arterial development, controlling proliferation of smooth muscle and stabilizing arterial structure.

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Figure 1: Disruption of the murine ELN gene.
Figure 2: Histology of different developmental stages in ELN+/+ and ELN−/− aortae.
Figure 3: Consequences of elastin deficiency in different arteries.
Figure 4: Mechanism of luminal obliteration in ELN−/− mice.
Figure 5: Organ culture of ELN+/+ and ELN−/− ascending aortae.

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Acknowledgements

We thank D. Atkinson for help with manuscript preparation; M. Parmacek, K.Thomas, R. White, S. Prescott, J. Kaplan, G. Zimmerman and M. Sanguinetti for comments; and K.Thomas for technical advice. ES cells and chimaeric mice were generated in M. R. Capecchi's laboratory. This work was supported by the NIH and by the Bristol-Myers Squibb Foundation.

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Correspondence to Dean Y. Li.

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Li, D., Brooke, B., Davis, E. et al. Elastin is an essential determinant of arterial morphogenesis. Nature 393, 276–280 (1998). https://doi.org/10.1038/30522

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