Molecular Genetics of Vascular Malformations

Abstract

Vascular anomalies are separated into vascular tumours and vascular malformations. Vascular malformations are named according to the affected type of vessels, that is venous, capillary, arteriovenous or lymphatic malformations. Up to now, sclerotherapy, embolisation and/or surgery are the treatments of choice, yet they do not often offer a curative treatment. Thus, there is an important need to develop novel disease‐specific therapeutic approaches. Inherited forms of vascular malformations led to the identification of several genes that are mutated encoding dysfunctional proteins. Demonstration that tissular second hits are commonly involved in inherited forms to explain development of lesions led to study somatic mutations in sporadically occurring forms. Since the primary discovery demonstrating that venous malformations are due to somatic mutations in TIE2/TEK, most types of vascular anomalies now have a known genetic cause. Thereby, the signalling pathways involved have been unravelled, leading to a better understanding of the aetiopathogenesis of vascular anomalies. As – like in cancers – the RAS/MAPK/ERK and the PI3K/AKT/mTOR signalling are enhanced in most vascular anomalies, treatment with cancer drugs interfering with these pathways could represent novel treatment options. Key Concepts Vascular anomalies are classified into tumours and malformations. The latter are further divided according to the affected vessels to capillary, venous, arterial, lymphatic and combined malformations. Treatment options are mostly restricted to sclerotherapy, embolisation and/or surgery. Most vascular anomalies are caused by genetic mutations, either germ line or somatic. Altered signalling involves RAS/MAPK/ERK, BMP9/10/ALK, PI3K/AKT/mTOR and VEGF/VEGFR3 pathways. Same pathways are also involved in cancers. Making repurposing of cancer drugs that interfere with these pathways, such as the mTOR inhibitor rapamycin, of interest for the treatment of vascular anomalies.

Emerging importance of molecular pathogenesis of vascular malformations in clinical practice and classifications

“…1 Vascular malformations occur during early vascular development, resulting in abnormally formed vessels that can manifest as arterial, venous, capillary or lymphatic lesions, or in combination, and include local tissue overdevelopment. These lesions are largely caused by sporadic somatic gene mutations 2 that regulate vital pathways such as angiogenesis, apoptosis, maturation, proliferation, and growth of vascular cells. 3 Vascular malformations are presumed to be present at birth but remain subclinical until presentation.…”

Multiple Gastrointestinal Vascular Variations in a Male Cadaver: A Case Report and Literature Review of Embryonic, Genetic, and Clinicosurgical Implications of Pathogenicity

“…The genetics of vascular development are complex and are currently under active investigation both in animal studies and in the deep whole-genome analysis. The major genes implicated during angiogenesis include PI3k/Akt [22], TGF-beta [23], TIE2/TEK [24], and TIE2/ TEK [25]. Among the gene mutations, implicated in vascular anomalies are those having an effect on endothelial proliferation, migration, attachment, stem cell differentiation, as well as survival [26].…”