The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC α-actin (encoded by ACTA2) and the β-myosin heavy chain (encoded by MYH11). Here we show that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (TAAD). Structural analyses and immunofluorescence of actin filaments in SMCs derived from individuals heterozygous for ACTA2 mutations illustrate that these mutations interfere with actin filament assembly and are predicted to decrease SMC contraction. Aortic tissues from affected individuals showed aortic medial degeneration, focal areas of medial SMC hyperplasia and disarray, and stenotic arteries in the vasa vasorum due to medial SMC proliferation. These data, along with the previously reported MYH11 mutations causing familial TAAD1, indicate the importance of SMC contraction in maintaining the structural integrity of the ascending aorta.
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The authors are grateful to the families and their physicians involved in this study, to S. Veeraraghavan for help generating the structure panels and to C. Akers for excellent graphic assistance. The following sources provided funding for these studies: RO1 HL62594 (D.M.M.), P50HL083794-01 (D.M.M.), UL1 RR024148 (CTSA), and TexGen Foundation. D.M.M. is a Doris Duke Distinguished Clinical Scientist. C.S.R. is a Pew Scholar. R.A.L. is a Senior Scientific Investigator of Research to Prevent Blindness, New York, New York.
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Guo, DC., Pannu, H., Tran-Fadulu, V. et al. Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet 39, 1488–1493 (2007). https://doi.org/10.1038/ng.2007.6
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