Venous malformations (VMs) are common congenital vascular anomalies that usually appear at birth or in childhood. Mutations in the tyrosine kinase with immunoglobulin-like and epidermal growth factor like (EGF-like) domains 2/phosphoinositide 3-kinase (TIE2/PI3K)-related genes within endothelial cells (ECs) disrupt EC function and phenotype. However, VMs do not merely manifest as abnormalities of ECs. Lesions typically feature dilated and tortuous vessels with stagnant blood flow, thrombi or phleboliths, and disorganized structural layers. Histological evidence shows that VMs involve a range of cellular and noncellular components, including ECs, vascular smooth muscle cells, immune cells, platelets, and the extracellular matrix. While gene mutations in ECs may pull the trigger, VM progression depends on complex interactions among various elements, complicating clinical management. Existing studies have identified individual clues (e.g., mutations, cell loss, matrix degradation). However, the failure to define the interlocking logic between these pieces has prevented the assembly of a coherent picture on VM pathophysiology. Developmental biology reveals that embryonic angiogenesis is governed by ECs through tightly regulated intercellular communication. Hijacking of this communication is increasingly recognized as key contributors to VM development. This review maps how intercellular communication—via secretory factors, extracellular vesicles, direct contact, and mechanobiology—coalesces into a cohesive network that drives VM progression, and evaluates these pathways as promising diagnostic and therapeutic targets.
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