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.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.

Cytochrome P4502E1 sensitizes to tumor necrosis factor alpha–induced liver injury through activation of mitogen-activated protein kinases in mice

“…Previous studies using specific cell types isolated from vascular lesions have identified a number of genes whose expression was altered in the lesion compared to normal skin including AKT1, HES/HEY transcription factors, HIF1A, and RASA1 10, 15–18, 58. None of our comparisons showed any significant difference in the expression of these genes.…”

Microarray analysis of port wine stains before and after pulsed dye laser treatment

“…Previous studies using specific cell types isolated from vascular lesions have identified a number of genes whose expression was altered in the lesion compared to normal skin including AKT1, HES/HEY transcription factors, HIF1A, and RASA1 [10,[15][16][17][18]58]. None of our comparisons showed any significant difference in the expression of these genes.…”

Sirolimus is highly effective for lymph leakage in microcystic lymphatic malformations with skin involvement

“…Some studies have found overexpression of genes in the mTOR signaling pathway in the endothelial cells of patients with vascular malformations. It is known that sirolimus has an inhibitory effect on lymphangiogenesis . It is also postulated that sirolimus has an influence on the circulation of lymph fluid in the body.…”