Genetics of vascular malformation and therapeutic implications

Abstract

Purpose of review Vascular malformations (VaMs) are a consequence of disrupted morphogenesis that may involve arterial, capillary, venous, or lymphatic endothelium alone or in a combination. VaMs can have serious health impacts, leading to life-threatening conditions sometimes. Genetic mutations affecting proliferation, migration, adhesion, differentiation, and survival of endothelial cells, as well as integrity of extracellular matrix are believed to be the pathogenesis of these disorders. Here, we present an updated review of genetic mutations and potential therapeutic targets for VaMs. Recent findings Increased number of genetic mutations have been discovered in vascular anomalies via targeted deep sequencing. When a genetic defect is identified, it often presents in only a small percentage of cells within the malformation. In addition, mutations within the same gene may result in different clinical phenotypes. Management of VaMs can be challenging depending on the severity and functional impairment associated. There are no standard treatment algorithms available to date for VaMs, therefore the disorder has significant unmet clinical needs. Currently, the focus of therapeutic development is to target constitutively activated intracellular signaling pathways resulted from genetic mutations. Summary Knowledge about the genetic mutations and altered signaling pathways related to VaMs have improved our understanding about the pathogenesis of vascular anomalies and provided insights to the development of new targeted therapies.

Efficacy and safety of sirolimus in the treatment of vascular malformations

“…The somatic mutation in PI3K/AKT/mTOR signaling pathway discovered in VMs, which is critical to cell growth and proliferation. [ 21 22 ] The new discoveries are the foundation for the treatment of VMs with sirolimus. Positive response with limited toxicity of sirolimus in treatment of VMs were reported in numerous reports,[ 11 23 24 ] but large prospective clinical trials are limited.…”

Pathogenesis of non-hereditary brain arteriovenous malformation and therapeutic implications

“…Loss of function mutations of RASA1 may therefore lead to activation of RAS and increased downstream signaling via the MEK-ERK1/2 and PI3K-AKT-mTOR pathways that can be potentially targeted. 88 Additional recent studies demonstrated autosomal dominant EPHB4 mutations, named CM-AVM2. 89 This gene encodes a trans-membrane receptor expressed primarily in venous ECs during vascular development interacting with its ligand, EphrinB2, on arterial ECs.…”

Management of Venous Malformations

“…1). [3][4][5] A gain-offunction somatic mutation in TEK leads to the overexpression of receptor tyrosine kinase TIE2, which is expressed on venous endothelial cells, resulting in dysplasia of the basement mem-brane and endothelium. While only seen in 25% of sporadic VMs, a somatic mutation in PIK3CA leads to unregulated activation of PI3K, which affects cell proliferation, migration, and survival.…”