TGF-β1 Promotes Angiogenesis via Endothelial-to-Mesenchymal Transition in Infantile Hemangioma

Abstract

BACKGROUND: Infantile hemangioma (IH) is the most common benign tumor in infancy and severely affects aesthetics and function. Hemangioma-derived endothelial cells (HemECs) are the main cellular component of IH and contribute to angiogenesis in IH. TGF-β1 (transforming growth factor β1) can induce endothelial-to-mesenchymal transition (EndoMT). Few studies have investigated the role and mechanism of TGF-β1-mediated EndoMT in IH angiogenesis. METHODS: The expression of EndoMT markers in IH samples was evaluated via multiplexed immunofluorescence assay. Lentiviruses and small interfering RNA were used to regulate gene expression. Targeted lipidomic analysis was subsequently conducted. Protein interactions between TGF-β1 and potential effectors were examined. Biological changes in function were measured by migration, invasion, and tube formation in vitro and vessel formation in vivo. Autophagy-related structures were detected via transmission electron microscopy. BALB/C-nu mice were used for the hemangioma model. RESULTS: In this study, the active participation of EndoMT in proliferating IH was verified. TGF-β1OE (TGF-β1 overexpression) induced EndoMT and promoted the migration, invasion, and angiogenic abilities of HemECs. In addition, TGF-β1OE decreased the protein expression of CPT1A (carnitine palmitoyltransferase 1A). TGF-β1 treatment decreased the levels of L-palmitoylcarnitine (a downstream metabolite of CPT1A) in HemECs. Supplementation with L-palmitoylcarnitine partly reversed the functional changes caused by CPT1AKD (CPT1A knockdown). Furthermore, the effect of TGF-β1OE+overexpression model of CPT1A was similar to that of CPT1AKD+L-palmitoylcarnitine in regulating the functional behaviors of HemECs. R(+) propranolol inhibited HemECs EndoMT and vessel formation in vivo. CONCLUSIONS: TGF-β1-mediated EndoMT promotes angiogenesis in IH. Targeting TGF-β1 could be a promising therapeutic strategy for inhibiting IH progression.