Cellular heterogeneity and tissue specificity in venous malformations: Implications for pathogenesis and targeted therapies

Abstract

Background

Venous malformations (VMs) are common vascular anomalies characterized by abnormal endothelial cell proliferation, a paucity of vascular wall cells, and irregular vascular structures. While pathogenic gene mutations are the genetic basis of VMs, the cellular heterogeneity, tissue specificity, and underlying mechanisms remain poorly understood. VMs are increasingly recognized as vascular anomalies with tumor-like mechanisms, highlighting the critical roles of cellular heterogeneity and tissue specificity in pathogenesis.

Methods

This review systematically examines recent advances in VMs research, focusing on cellular heterogeneity and tissue specificity. It summarizes key mutated genes, the roles of various cell types, and their interactions within lesions. By comparing physiological differences between arteries and veins, we explore the tissue-specific origins of VMs. Additionally, we evaluate current cellular and animal models, discussing their strengths and limitations in simulating pathological features, including cellular heterogeneity and tissue specificity.

Results

The development of VMs is strongly linked to genetic mutations in endothelial cells, as well as functional alterations in endothelial progenitor cells, vascular wall cells, and other perivascular cells. Lesion tissues exhibit significant heterogeneity in cell function, gene/protein expression, and signal transduction. Tissue specificity is influenced by differences in environmental factors, tissue structure, and gene expression between arteries and veins, explaining why VMs predominantly affect veins.

Conclusions

VMs development involves interactions among pathogenic gene mutations, cellular heterogeneity, and tissue specificity. Understanding these mechanisms will elucidate VMs pathogenesis and inform precision therapies. Future research should focus on cell-type interactions, the role of tissue specificity in disease progression, and developing targeted therapeutic strategies.