Phenotypic Transition of Vascular Smooth Muscle Cells Induced by Endothelial TIE2 Mutations in Venous Malformations

Abstract Venous malformations (VMs) are congenital vascular malformations characterized by a chronically enlarged and malformed venous cavity. Although TIE2 mutation has been commonly recognized as a vital genetic landscape in VMs, the role of TIE2 in regulating the contraction function of smooth muscle cells remains unclear. We generated mouse models through endothelial germline/somatic expression of Tie2-R848W, which has been identified as a typical mutation in autosomal inherited venous malformations, multiple cutaneous and mucosal venous malformation (VMCM). Tie2-R848Wfl/fl;Tie2Cre+ mice develop pulmonary vascular malformations with internal hemorrhage. Tie2-R848W in Tie2-R848Wfl/fl;AplnER+ mice induces postnatal retinal vascular malformations. Accordingly, we demonstrate that dysregulated function and phenotypic transition of vascular smooth muscle cells (VSMCs) may be the pathogenic basis of Tie2-related vascular malformations. The phenotypic transition of VSMCs was further identified in human VMs of the head and neck carrying TIE2 mutations and in an in vitro model. Downregulated ion transmembrane transport and TNFSF10 may play a substantial role in initiating the phenotypic transition process of VSMCs. In conclusion, germline/somatic TIE2 mutation in ECs might induce an abnormal regulatory relationship between ECs and VSMCs, which is highly associated with the phenotypic transition of VSMCs. Weakened contractility and abnormal proliferation induce a chronic expansion cavity and thickening of the muscle layer, which may develop into venous malformation.