title: Aortic aneurysm generation in mice with targeted deletion of integrin-linked kinase in vascular smooth muscle cells.
abstract: BACKGROUND
  Integrin-linked kinase (ILK) is located at focal adhesions and links the extracellular matrix (ECM) to the actin cytoskeleton via β1- and β3-integrins. ILK plays a role in the activation of kinases including protein kinase B/Akt and glycogen synthase kinase 3β and regulates cell proliferation, motility, and survival.
  
  
  OBJECTIVE
  To determine the function of ILK in vascular smooth muscle cells (SMCs) in vivo.
  
  
  RESULTS
  SM22Cre(+)Ilk(Fl/Fl) conditional mutant mice were generated in which the Ilk gene was selectively ablated in SMCs. SM22Cre(+)Ilk(Fl/Fl) conditional mutant mice survive to birth but die in the perinatal period exhibiting multiple vascular pathologies including aneurysmal dilatation of the aorta and patent ductus arteriosus (PDA). Defects in morphogenetic development of the aorta were observed as early as E12.5 in SM22Cre(+)Ilk(Fl/Fl) mutant embryos. By late gestation (E16.5 to 18.5), striking expansion of the thoracic aorta was observed in ILK mutant embryos. Histological analyses revealed that the structural organization of the arterial tunica media is severely disrupted with profound derangements in SMC morphology, cell-cell, and cell-matrix relationships, including disruption of the elastic lamellae. ILK deletion in primary aortic SMCs results in alterations of RhoA/cytoskeletal signaling transduced through aberrant localization of myocardin-related transcription factor (MRTF)-A repressing the transcription and expression of SMC genes, which are required for the maintenance of the contractile SMC phenotype.
  
  
  CONCLUSIONS
  These data identify a molecular pathway linking ILK signaling to the contractile SMC gene program. Activation of this pathway is required for morphogenetic development of the aorta and ductus arteriosus during embryonic and postnatal survival.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital East-8307, Charlestown, MA 02129, USA.
authors.forename: Dongxiao
authors.initials: D
authors.lastname: Shen
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: John J
authors.initials: JJ
authors.lastname: Lepore
authors.forename: Thomas J T
authors.initials: TJ
authors.lastname: Anderson
authors.forename: Sumita
authors.initials: S
authors.lastname: Sinha
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Lin
authors.forename: Lan
authors.initials: L
authors.lastname: Cheng
authors.forename: Ethan David
authors.initials: ED
authors.lastname: Cohen
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Roberts
authors.forename: Shoukat
authors.initials: S
authors.lastname: Dedhar
authors.forename: Michael S
authors.initials: MS
authors.lastname: Parmacek
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
mesh_terms: D000818:Animals; D001014:Aortic Aneurysm / Q000201:enzymology* / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D017353:Gene Deletion; D018390:Gene Targeting / Q000379:methods; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics*; D000099200:Scaffold Protein ILK
chemical_list: D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK