Pathophysiology of Slow-Flow Vascular Malformations: Current Understanding and Unanswered Questions

Abstract

Background: Slow-flow vascular malformations include venous, lymphatic, and lymphaticovenous malformations. Recent studies have linked genetic variants hyperactivating either the PI3K/AKT/mTOR and/or RAS/RAF/MAPK signaling pathways with slow-flow vascular malformation development, leading to the use of pharmacotherapies such as sirolimus and alpelisib. It is important that clinicians understand basic and translational research advances in slow-flow vascular malformations. Methods: A literature review of basic science publications in slow-flow vascular malformations was performed on Pubmed, using search terms “venous malformation,” “lymphatic malformation,” “lymphaticovenous malformation,” “genetic variant,” “genetic mutation,” “endothelial cells,” and “animal model.” Relevant publications were reviewed and summarized. Results: The study of patient tissues and the use of primary pathogenic endothelial cells from vascular malformations shed light on their pathological behaviors, such as endothelial cell hyperproliferation and disruptions in vessel architecture. The use of xenograft and transgenic animal models confirmed the pathogenicity of genetic variants and allowed for preclinical testing of potential therapies. These discoveries underscore the importance of basic and translational research in understanding the pathophysiology of vascular malformations, which will allow for the development of improved biologically targeted treatments. Conclusion: Despite basic and translation advances, a cure for slow-flow vascular malformations remains elusive. Many questions remain unanswered, including how genotype variants result in phenotypes, and genotype-phenotype heterogeneity. Continued research into venous and lymphatic malformation pathobiology is critical in understanding the mechanisms by which genetic variants contribute to vascular malformation phenotypic features.