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AKT1 Overexpression in Endothelial Cells Leads to the Development of Cutaneous Vascular Malformations In Vivo
Betsy Perry, MD;
Jacqueline Banyard, PhD;
Elizabeth R. McLaughlin, MD;
Randy Watnick, PhD;
Allie Sohn, BS;
David N. Brindley, PhD;
Toshiyuki Obata, PhD;
Lewis C. Cantley, PhD;
Cynthia Cohen, MD;
Jack L. Arbiser, MD, PhD
Arch Dermatol. 2007;143(4):504-506.
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.
Observations 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.
Author Affiliations: Department of Dermatology, Emory University School of Medicine, Atlanta, Ga (Drs Perry, McLaughlin, Cohen, and Arbiser and Ms Sohn); Vascular Biology Program, Department of Surgery, Children's Hospital Boston (Drs Banyard and Watnick), and Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center (Drs Obata and Cantley), Harvard Medical School, Boston, Mass; Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology (Drs Obata and Cantley), Cambridge; and Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton (Dr Brindley).
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