title: Deficient Circumferential Growth Is the Primary Determinant of Aortic Obstruction Attributable to Partial Elastin Deficiency.
abstract: Williams syndrome is characterized by obstructive aortopathy attributable to heterozygous loss ofELN, the gene encoding elastin. Lesions are thought to result primarily from excessive smooth muscle cell (SMC) proliferation and consequent medial expansion, although an initially smaller caliber and increased stiffness of the aorta may contribute to luminal narrowing. The relative contributions of such abnormalities to the obstructive phenotype had not been defined.
  
  
  
  We quantified determinants of luminal stenosis in thoracic aortas ofEln-/-mice incompletely rescued by humanELN. Moderate obstruction was largely because of deficient circumferential growth, most prominently of ascending segments, despite increased axial growth. Medial thickening was evident in these smaller diameter elastin-deficient aortas, with medial area similar to that of larger diameter control aortas. There was no difference in cross-sectional SMC number between mutant and wild-type genotypes at multiple stages of postnatal development. Decreased elastin content was associated with medial fibrosis and reduced aortic distensibility because of increased structural stiffness but preserved material stiffness. Elastin-deficient SMCs exhibited greater contractile-to-proliferative phenotypic modulation in vitro than in vivo. We confirmed increased medial collagen without evidence of increased medial area or SMC number in a small ascending aorta with thickened media of a Williams syndrome subject.
  
  
  
  Deficient circumferential growth is the predominant mechanism for moderate obstructive aortic disease resulting from partial elastin deficiency. Our findings suggest that diverse aortic manifestations in Williams syndrome result from graded elastin content, and SMC hyperplasia causing medial expansion requires additional elastin loss superimposed onELNhaploinsufficiency.
authors.affiliation: From the Department of Surgery, Yale University School of Medicine, New Haven, CT (Y.J., G.L., L.Q., Q.L., W.L., G.T.); Department of Vascular Surgery, Peking University People's Hospital, Beijing, People's Republic of China (Y.J., Q.L., W.L.); Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China (G.L.); Department of Biomedical Engineering, Yale University, New Haven, CT (A.K., A.W.C., M.R.B., J.D.H.); Department of Cell Biology, Washington University School of Medicine, St Louis, MO (R.P.M.); Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine (J.D.H., G.T.); and Veterans Affairs Connecticut Healthcare System, West Haven (G.T.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: From the Department of Surgery, Yale University School of Medicine, New Haven, CT (Y.J., G.L., L.Q., Q.L., W.L., G.T.); Department of Vascular Surgery, Peking University People's Hospital, Beijing, People's Republic of China (Y.J., Q.L., W.L.); Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China (G.L.); Department of Biomedical Engineering, Yale University, New Haven, CT (A.K., A.W.C., M.R.B., J.D.H.); Department of Cell Biology, Washington University School of Medicine, St Louis, MO (R.P.M.); Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine (J.D.H., G.T.); and Veterans Affairs Connecticut Healthcare System, West Haven (G.T.).
authors.forename: Guangxin
authors.initials: G
authors.lastname: Li
authors.affiliation: From the Department of Surgery, Yale University School of Medicine, New Haven, CT (Y.J., G.L., L.Q., Q.L., W.L., G.T.); Department of Vascular Surgery, Peking University People's Hospital, Beijing, People's Republic of China (Y.J., Q.L., W.L.); Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China (G.L.); Department of Biomedical Engineering, Yale University, New Haven, CT (A.K., A.W.C., M.R.B., J.D.H.); Department of Cell Biology, Washington University School of Medicine, St Louis, MO (R.P.M.); Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine (J.D.H., G.T.); and Veterans Affairs Connecticut Healthcare System, West Haven (G.T.).
authors.forename: Arina
authors.initials: A
authors.lastname: Korneva
authors.affiliation: From the Department of Surgery, Yale University School of Medicine, New Haven, CT (Y.J., G.L., L.Q., Q.L., W.L., G.T.); Department of Vascular Surgery, Peking University People's Hospital, Beijing, People's Republic of China (Y.J., Q.L., W.L.); Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China (G.L.); Department of Biomedical Engineering, Yale University, New Haven, CT (A.K., A.W.C., M.R.B., J.D.H.); Department of Cell Biology, Washington University School of Medicine, St Louis, MO (R.P.M.); Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine (J.D.H., G.T.); and Veterans Affairs Connecticut Healthcare System, West Haven (G.T.).
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Caulk
authors.affiliation: From the Department of Surgery, Yale University School of Medicine, New Haven, CT (Y.J., G.L., L.Q., Q.L., W.L., G.T.); Department of Vascular Surgery, Peking University People's Hospital, Beijing, People's Republic of China (Y.J., Q.L., W.L.); Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China (G.L.); Department of Biomedical Engineering, Yale University, New Haven, CT (A.K., A.W.C., M.R.B., J.D.H.); Department of Cell Biology, Washington University School of Medicine, St Louis, MO (R.P.M.); Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine (J.D.H., G.T.); and Veterans Affairs Connecticut Healthcare System, West Haven (G.T.).
authors.forename: Lingfeng
authors.initials: L
authors.lastname: Qin
authors.affiliation: From the Department of Surgery, Yale University School of Medicine, New Haven, CT (Y.J., G.L., L.Q., Q.L., W.L., G.T.); Department of Vascular Surgery, Peking University People's Hospital, Beijing, People's Republic of China (Y.J., Q.L., W.L.); Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China (G.L.); Department of Biomedical Engineering, Yale University, New Haven, CT (A.K., A.W.C., M.R.B., J.D.H.); Department of Cell Biology, Washington University School of Medicine, St Louis, MO (R.P.M.); Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine (J.D.H., G.T.); and Veterans Affairs Connecticut Healthcare System, West Haven (G.T.).
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Bersi
authors.affiliation: From the Department of Surgery, Yale University School of Medicine, New Haven, CT (Y.J., G.L., L.Q., Q.L., W.L., G.T.); Department of Vascular Surgery, Peking University People's Hospital, Beijing, People's Republic of China (Y.J., Q.L., W.L.); Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China (G.L.); Department of Biomedical Engineering, Yale University, New Haven, CT (A.K., A.W.C., M.R.B., J.D.H.); Department of Cell Biology, Washington University School of Medicine, St Louis, MO (R.P.M.); Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine (J.D.H., G.T.); and Veterans Affairs Connecticut Healthcare System, West Haven (G.T.).
authors.forename: Qingle
authors.initials: Q
authors.lastname: Li
authors.affiliation: From the Department of Surgery, Yale University School of Medicine, New Haven, CT (Y.J., G.L., L.Q., Q.L., W.L., G.T.); Department of Vascular Surgery, Peking University People's Hospital, Beijing, People's Republic of China (Y.J., Q.L., W.L.); Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China (G.L.); Department of Biomedical Engineering, Yale University, New Haven, CT (A.K., A.W.C., M.R.B., J.D.H.); Department of Cell Biology, Washington University School of Medicine, St Louis, MO (R.P.M.); Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine (J.D.H., G.T.); and Veterans Affairs Connecticut Healthcare System, West Haven (G.T.).
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: From the Department of Surgery, Yale University School of Medicine, New Haven, CT (Y.J., G.L., L.Q., Q.L., W.L., G.T.); Department of Vascular Surgery, Peking University People's Hospital, Beijing, People's Republic of China (Y.J., Q.L., W.L.); Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China (G.L.); Department of Biomedical Engineering, Yale University, New Haven, CT (A.K., A.W.C., M.R.B., J.D.H.); Department of Cell Biology, Washington University School of Medicine, St Louis, MO (R.P.M.); Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine (J.D.H., G.T.); and Veterans Affairs Connecticut Healthcare System, West Haven (G.T.).
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mecham
authors.affiliation: From the Department of Surgery, Yale University School of Medicine, New Haven, CT (Y.J., G.L., L.Q., Q.L., W.L., G.T.); Department of Vascular Surgery, Peking University People's Hospital, Beijing, People's Republic of China (Y.J., Q.L., W.L.); Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China (G.L.); Department of Biomedical Engineering, Yale University, New Haven, CT (A.K., A.W.C., M.R.B., J.D.H.); Department of Cell Biology, Washington University School of Medicine, St Louis, MO (R.P.M.); Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine (J.D.H., G.T.); and Veterans Affairs Connecticut Healthcare System, West Haven (G.T.).
authors.forename: Jay D
authors.initials: JD
authors.lastname: Humphrey
authors.affiliation: From the Department of Surgery, Yale University School of Medicine, New Haven, CT (Y.J., G.L., L.Q., Q.L., W.L., G.T.); Department of Vascular Surgery, Peking University People's Hospital, Beijing, People's Republic of China (Y.J., Q.L., W.L.); Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China (G.L.); Department of Biomedical Engineering, Yale University, New Haven, CT (A.K., A.W.C., M.R.B., J.D.H.); Department of Cell Biology, Washington University School of Medicine, St Louis, MO (R.P.M.); Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine (J.D.H., G.T.); and Veterans Affairs Connecticut Healthcare System, West Haven (G.T.). george.tellides@yale.edu.
authors.forename: George
authors.initials: G
authors.lastname: Tellides
mesh_terms: D000328:Adult; D000818:Animals; D001013:Aorta, Thoracic / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D004549:Elastin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006801:Humans; D006965:Hyperplasia; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D013997:Time Factors; D059289:Vascular Stiffness; D014661:Vasoconstriction; D018980:Williams Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
chemical_list: D003094:Collagen; D004549:Elastin
keywords: aorta; collagen; elastin; smooth muscle cells; vascular remodeling