Venous malformations: from causes to pathogenic mechanisms and murine models

Abstract

Vascular malformations are localized errors of vascular development. They are often identified on the skin as “birthmarks” of various sizes and shapes but may be encountered in other organs, such as the liver, intestine and the brain. Venous malformations are the most commonly seen vascular malformations in specialized multidisciplinary centers, due to associated morbidity. Most are sporadic, but familial forms exist: VMCM, for mucocutaneous venous malformation, and GVM, for glomuvenous malformation. We unravelled that these hereditary forms are basically caused by a dominant activating TIE2 mutation (VMCM) or a loss‐of‐function glomulin mutation (GVM). The large clinical variability regarding the location, number and size of lesions, made us hypothesize that a somatic second‐hit may be needed, as suggested by Knudson for retinoblastoma. Proof for this has started to pile up. Moreover, our tissular screens have also identified local, somatic genetic defects that cause the most common sporadic form of venous malformations. These mutations differ from the inherited ones in regard to hyperphosphorylating effects and downstream transcriptomic profiles when expressed in HUVECs. These data highlight the importance of assessing for tissue‐based genetic changes, especially acquired genetic changes, as possible pathophysiological causes, which have been largely overlooked in developmental disorders.