title: AKT1 overexpression in endothelial cells leads to the development of cutaneous vascular malformations in vivo.
abstract: BACKGROUND
  Vascular malformations are clinical disorders in which endothelial cells fail to remodel and/or undergo programmed cell death, leading to abnormal persistence of blood vessels. The abnormal persistence of vessels makes therapy difficult because these lesions are resistant to interventions that are effective against hemangiomas. Akt1 is a serine-threonine protein kinase, which is a key mediator of resistance to programmed cell death. Our objective was to determine whether sustained activation of Akt1 could lead to vascular malformation in mice.
  
  
  METHODS
  We examined the effect of constitutive activation of Akt1 in murine endothelial cells (MS1 cells). Overexpression of active AKT1 in MS1 cells led to the development of vascular malformations, characterized by wide endothelial lumens and minimal investment of smooth muscle surrounding the vessels. The histologic features of these vascular malformations is distinct from ras-transformed MS1 cells (angiosarcoma) and suggest that differing signal abnormalities give rise to human vascular malformations vs malignant vascular tumors.
  
  
  CONCLUSIONS
  Inhibition of Akt signaling may be useful in the treatment of vascular malformations. Examination of problematic hemangiomas and vascular malformations for the presence of activated Akt or downstream targets of Akt, such as mammalian target of rapamycin (mTOR), may predict response to treatment with Akt inhibitors or rapamycin. This study provides a potential rationale for the systemic and topical use of these inhibitors for vascular malformations and hemangiomas.
authors: Department of Dermatology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Betsy
authors: B
authors: Perry
authors: Jacqueline
authors: J
authors: Banyard
authors: Elizabeth R
authors: ER
authors: McLaughlin
authors: Randy
authors: R
authors: Watnick
authors: Allie
authors: A
authors: Sohn
authors: David N
authors: DN
authors: Brindley
authors: Toshiyuki
authors: T
authors: Obata
authors: Lewis C
authors: LC
authors: Cantley
authors: Cynthia
authors: C
authors: Cohen
authors: Jack L
authors: JL
authors: Arbiser
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities*; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism / Q000637:transplantation; D004730:Endothelium, Vascular / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012867:Skin / Q000098:blood supply*
chemical_list: C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt