Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Nov 15;102(10):1783–1787. doi: 10.1172/JCI4487

Novel arterial pathology in mice and humans hemizygous for elastin.

D Y Li 1, G Faury 1, D G Taylor 1, E C Davis 1, W A Boyle 1, R P Mecham 1, P Stenzel 1, B Boak 1, M T Keating 1
PMCID: PMC509127  PMID: 9819363

Abstract

Obstructive vascular disease is an important health problem in the industrialized world. Through a series of molecular genetic studies, we demonstrated that loss-of-function mutations in one elastin allele cause an inherited obstructive arterial disease, supravalvular aortic stenosis (SVAS). To define the mechanism of elastin's effect, we generated mice hemizygous for the elastin gene (ELN +/-). Although ELN mRNA and protein were reduced by 50% in ELN +/- mice, arterial compliance at physiologic pressures was nearly normal. This discrepancy was explained by a paradoxical increase of 35% in the number of elastic lamellae and smooth muscle in ELN +/- arteries. Examination of humans with ELN hemizygosity revealed a 2. 5-fold increase in elastic lamellae and smooth muscle. Thus, ELN hemizygosity in mice and humans induces a compensatory increase in the number of rings of elastic lamellae and smooth muscle during arterial development. Humans are exquisitely sensitive to reduced ELN expression, developing profound arterial thickening and markedly increased risk of obstructive vascular disease.

Full Text

The Full Text of this article is available as a PDF (480.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Boyle W. A., 3rd, Maher G. M. Endothelium-independent vasoconstricting and vasodilating actions of halothane on rat mesenteric resistance blood vessels. Anesthesiology. 1995 Jan;82(1):221–235. doi: 10.1097/00000542-199501000-00027. [DOI] [PubMed] [Google Scholar]
  2. Chan G. M., Buchino J. J., Mehlhorn D., Bove K. E., Steichen J. J., Tsang R. C. Effect of vitamin D on pregnant rabbits and their offspring. Pediatr Res. 1979 Feb;13(2):121–126. doi: 10.1203/00006450-197902000-00007. [DOI] [PubMed] [Google Scholar]
  3. Curran M. E., Atkinson D. L., Ewart A. K., Morris C. A., Leppert M. F., Keating M. T. The elastin gene is disrupted by a translocation associated with supravalvular aortic stenosis. Cell. 1993 Apr 9;73(1):159–168. doi: 10.1016/0092-8674(93)90168-p. [DOI] [PubMed] [Google Scholar]
  4. Davis E. C. Elastic lamina growth in the developing mouse aorta. J Histochem Cytochem. 1995 Nov;43(11):1115–1123. doi: 10.1177/43.11.7560894. [DOI] [PubMed] [Google Scholar]
  5. Davis E. C. Smooth muscle cell to elastic lamina connections in developing mouse aorta. Role in aortic medial organization. Lab Invest. 1993 Jan;68(1):89–99. [PubMed] [Google Scholar]
  6. Dietz H. C., Pyeritz R. E. Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders. Hum Mol Genet. 1995;4(Spec No):1799–1809. doi: 10.1093/hmg/4.suppl_1.1799. [DOI] [PubMed] [Google Scholar]
  7. Ewart A. K., Jin W., Atkinson D., Morris C. A., Keating M. T. Supravalvular aortic stenosis associated with a deletion disrupting the elastin gene. J Clin Invest. 1994 Mar;93(3):1071–1077. doi: 10.1172/JCI117057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ewart A. K., Morris C. A., Atkinson D., Jin W., Sternes K., Spallone P., Stock A. D., Leppert M., Keating M. T. Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet. 1993 Sep;5(1):11–16. doi: 10.1038/ng0993-11. [DOI] [PubMed] [Google Scholar]
  9. Friedman W. F., Roberts W. C. Vitamin D and the supravalvar aortic stenosis syndrome. The transplacental effects of vitamin D on the aorta of the rabbit. Circulation. 1966 Jul;34(1):77–86. doi: 10.1161/01.cir.34.1.77. [DOI] [PubMed] [Google Scholar]
  10. Hinek A., Botney M. D., Mecham R. P., Parks W. C. Inhibition of tropoelastin expression by 1,25-dihydroxyvitamin D3. Connect Tissue Res. 1991;26(3):155–166. doi: 10.3109/03008209109152434. [DOI] [PubMed] [Google Scholar]
  11. Li D. Y., Brooke B., Davis E. C., Mecham R. P., Sorensen L. K., Boak B. B., Eichwald E., Keating M. T. Elastin is an essential determinant of arterial morphogenesis. Nature. 1998 May 21;393(6682):276–280. doi: 10.1038/30522. [DOI] [PubMed] [Google Scholar]
  12. Li D. Y., Toland A. E., Boak B. B., Atkinson D. L., Ensing G. J., Morris C. A., Keating M. T. Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis. Hum Mol Genet. 1997 Jul;6(7):1021–1028. doi: 10.1093/hmg/6.7.1021. [DOI] [PubMed] [Google Scholar]
  13. Löhler J., Timpl R., Jaenisch R. Embryonic lethal mutation in mouse collagen I gene causes rupture of blood vessels and is associated with erythropoietic and mesenchymal cell death. Cell. 1984 Sep;38(2):597–607. doi: 10.1016/0092-8674(84)90514-2. [DOI] [PubMed] [Google Scholar]
  14. Machii M., Becker A. E. Hypoplastic aortic arch morphology pertinent to growth after surgical correction of aortic coarctation. Ann Thorac Surg. 1997 Aug;64(2):516–520. doi: 10.1016/S0003-4975(97)00444-X. [DOI] [PubMed] [Google Scholar]
  15. O'Connor W. N., Davis J. B., Jr, Geissler R., Cottrill C. M., Noonan J. A., Todd E. P. Supravalvular aortic stenosis. Clinical and pathologic observations in six patients. Arch Pathol Lab Med. 1985 Feb;109(2):179–185. [PubMed] [Google Scholar]
  16. Olson T. M., Michels V. V., Urban Z., Csiszar K., Christiano A. M., Driscoll D. J., Feldt R. H., Boyd C. D., Thibodeau S. N. A 30 kb deletion within the elastin gene results in familial supravalvular aortic stenosis. Hum Mol Genet. 1995 Sep;4(9):1677–1679. doi: 10.1093/hmg/4.9.1677. [DOI] [PubMed] [Google Scholar]
  17. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993 Apr 29;362(6423):801–809. doi: 10.1038/362801a0. [DOI] [PubMed] [Google Scholar]
  18. Vijayakumar S. T., Kurup P. A. Hypervitaminosis D and glycosaminoglycan metabolism in rats fed normal and high fat cholesterol diets. J Nutr. 1974 Apr;104(4):423–429. doi: 10.1093/jn/104.4.423. [DOI] [PubMed] [Google Scholar]
  19. WOLINSKY H., GLAGOV S. STRUCTURAL BASIS FOR THE STATIC MECHANICAL PROPERTIES OF THE AORTIC MEDIA. Circ Res. 1964 May;14:400–413. doi: 10.1161/01.res.14.5.400. [DOI] [PubMed] [Google Scholar]
  20. Wolinsky H., Glagov S. A lamellar unit of aortic medial structure and function in mammals. Circ Res. 1967 Jan;20(1):99–111. doi: 10.1161/01.res.20.1.99. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES