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.

A noncoding antisense RNA in tie-1 locus regulates tie-1 function in vivo

“…[29][30][31][32][33] To investigate whether the human tie-1AS lncRNA levels are altered in vascular malformation, we performed quantitative PCR for tie-1 and tie-1AS lncRNA on RNA isolated from vascular anomaly 34 tissue from 12 patients previously diagnosed for various anomalies and compared them with RNA from normal placenta. In general, placenta share several markers with hemangioma tissue 35 and therefore were used for comparisons.…”

Snrk-1 is involved in multiple steps of angioblast development and acts via notch signaling pathway in artery-vein specification in vertebrates

“…It is not known whether snrk-1 triggers cell survival pathways in endothelial cells, such as in the AKT pathway, but is worth investigating because akt1 overexpression in endothelial cells has resulted in the development of cutaneous vascular malformations in vivo. 22 In addition, the exclusivity of the snrk-1 mutations in venous or lymphatic malformation patient samples argues that snrk-1 may be an important molecular marker like wt-1 that helps distinguish vascular malformations from proliferative endothelial lesions. 23 In summary, this study reports a novel cytoplasmic signaling member of the Ser/Thr kinase family that plays a critical role in angioblast development in vertebrates in vivo.…”

Vascular-targeted agents for the treatment of angiosarcoma

“…pathway in SVR cells did result in significantly smaller angiosarcoma tumours in vivo [128], although independent over expression of Akt1 in murine endothelial cells resulted in benign vascular malformations distinct from angiosarcomas [130]. The viral oncogene v-p3k, of the avian sarcoma virus ASV16, codes for a gene homologous to the catalytic subunit of PI-3-kinase.…”