title: Rapamycin inhibits smooth muscle cell proliferation and obstructive arteriopathy attributable to elastin deficiency.
abstract: OBJECTIVE
  Patients with elastin deficiency attributable to gene mutation (supravalvular aortic stenosis) or chromosomal microdeletion (Williams syndrome) are characterized by obstructive arteriopathy resulting from excessive smooth muscle cell (SMC) proliferation, mural expansion, and inadequate vessel size. We investigated whether rapamycin, an inhibitor of the cell growth regulator mammalian target of rapamycin (mTOR) and effective against other SMC proliferative disorders, is of therapeutic benefit in experimental models of elastin deficiency.
  
  
  RESULTS
  As previously reported, Eln(-/-) mice demonstrated SMC hyperplasia and severe stenosis of the aorta, whereas Eln(+/-) mice exhibited a smaller diameter aorta with more numerous but thinner elastic lamellae. Increased mTOR signaling was detected in elastin-deficient aortas of newborn pups that was inhibited by maternal administration of rapamycin. mTOR inhibition reduced SMC proliferation and aortic obstruction in Eln(-/-) pups and prevented medial hyperlamellation in Eln(+/-) weanlings without compromising aortic size. However, rapamycin did not prolong the survival of Eln(-/-) pups, and it retarded the somatic growth of juvenile Eln(+/-) and Eln(+/+) mice. In cell cultures, rapamycin inhibited prolonged mTOR activation and enhanced proliferation of SMC derived from patients with supravalvular aortic stenosis and with Williams syndrome.
  
  
  CONCLUSIONS
  mTOR inhibition may represent a pharmacological strategy to treat diffuse arteriopathy resulting from elastin deficiency.
authors.affiliation: Department of Surgery, Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Qingle
authors.initials: Q
authors.lastname: Li
authors.forename: Lingfeng
authors.initials: L
authors.lastname: Qin
authors.forename: Rahmat
authors.initials: R
authors.lastname: Ali
authors.forename: Yibing
authors.initials: Y
authors.lastname: Qyang
authors.forename: May
authors.initials: M
authors.lastname: Tassabehji
authors.forename: Barbara R
authors.initials: BR
authors.lastname: Pober
authors.forename: William C
authors.initials: WC
authors.lastname: Sessa
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Giordano
authors.forename: George
authors.initials: G
authors.lastname: Tellides
mesh_terms: D000328:Adult; D000818:Animals; D021921:Aortic Stenosis, Supravalvular / Q000150:complications; D001157:Arterial Occlusive Diseases / Q000209:etiology* / Q000517:prevention & control; D049109:Cell Proliferation / Q000187:drug effects; D004549:Elastin / Q000172:deficiency*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D018980:Williams Syndrome / Q000150:complications
chemical_list: D004549:Elastin; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus