title: Fibulin-4 deficiency results in ascending aortic aneurysms: a potential link between abnormal smooth muscle cell phenotype and aneurysm progression.
abstract: BACKGROUND
  Loss of fibulin-4 during embryogenesis results in perinatal lethality because of aneurysm rupture, and defective elastic fiber assembly has been proposed as an underlying cause for the aneurysm phenotype. However, aneurysms are never seen in mice deficient for elastin, or for fibulin-5, which absence also leads to compromised elastic fibers.
  
  
  OBJECTIVE
  We sought to determine the mechanism of aneurysm development in the absence of fibulin-4 and establish the role of fibulin-4 in aortic development.
  
  
  RESULTS
  We generated germline and smooth muscle cell (SMC)-specific deletion of the fibulin-4 gene in mice (Fbln4(GKO) and Fbln4(SMKO), respectively). Fbln4(GKO) and Fbln4(SMKO) aortic walls fail to fully differentiate, exhibiting reduced expression of SM-specific contractile genes and focal proliferation of SMCs accompanied by degenerative changes of the medial wall. Marked upregulation of extracellular signal-regulated kinase 1/2 signaling pathway was observed in the aneurysmal wall of Fbln4(GKO) and Fbln4(SMKO) mice and both mutants developed aneurysm predominantly in the ascending thoracic aorta. In vitro, Fbln4(GKO) SMCs exhibit an immature SMC phenotype with a marked reduction of SM-myosin heavy chain and increased proliferative capacity.
  
  
  CONCLUSIONS
  The vascular phenotype in Fbln4 mutant mice is remarkably similar to a subset of human thoracic aortic aneurysms caused by mutations in SMC contractile genes. Our study provides a potential link between the intrinsic properties of SMCs and aneurysm progression in vivo and supports the dual role of fibulin-4 in the formation of elastic fibers as well as terminal differentiation and maturation of SMCs in the aortic wall.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Huang
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Davis
authors.forename: Shelby L
authors.initials: SL
authors.lastname: Chapman
authors.forename: Madhusudhan
authors.initials: M
authors.lastname: Budatha
authors.forename: Lihua Y
authors.initials: LY
authors.lastname: Marmorstein
authors.forename: R Ann
authors.initials: RA
authors.lastname: Word
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yanagisawa
mesh_terms: D000818:Animals; D001011:Aorta / Q000196:embryology / Q000473:pathology*; D001014:Aortic Aneurysm / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D003433:Crosses, Genetic; D004547:Elastic Tissue / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D005260:Female; D018095:Germ-Line Mutation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000473:pathology*; D009928:Organ Specificity; D017540:Tunica Media / Q000473:pathology
chemical_list: C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins