Apolipoprotein A-I Binding Protein Inhibits the Formation of Infantile Hemangioma through Cholesterol-Regulated Hypoxia-Inducible Factor 1α Activation

Abstract

Infantile hemangioma (IH) is the most frequent vascular tumor of infancy with unclear pathogenesis, of which disordered angiogenesis is considered to involve IH formation. We previously found that apolipoprotein A-I binding protein (AIBP)-also known as NAXE (NAD (P)HX epimerase)-a regulator of cholesterol metabolism, plays a critical role in the pathological angiogenesis of mammals. Here, we found that AIBP had much lower expression levels in both IH patients' tissues and hemangioma endothelial cells (HemECs), compared to adjacent normal tissues and human dermal vascular endothelial cells (HDMECs), respectively. Knockout of NAXE by CRISPR-Cas9 in HemECs enhanced tube formation and migration, and NAXE overexpression impaired tube formation and migration of HemECs. Interestingly, AIBP suppressed the proliferation of HemECs in hypoxia. We then found that reduced expression of AIBP correlated with increased Hif1α levels in IH patients' tissues and HemECs. Further mechanistic investigation demonstrated that AIBP disrupted Hif1α signaling via cholesterol metabolism under hypoxia. Notably, AIBP significantly inhibited the development of IH in immunodeficient mice. Furthermore, using the validated mouse endothelial cell (EOMA) and NAXE-/- mouse models, we demonstrated that both endogenous AIBP from tumors and AIBP in the tumor microenvironment limit the formation of hemangioma. These findings suggested that AIBP was a player in the pathogenesis of IH and could be a potential pharmacological target for treating IH.