Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma

Infantile hemangiomas are localized and rapidly growing regions of disorganized angiogenesis. We show that expression of vascular endothelial growth factor receptor-1 (VEGFR1/Flt-1) in hemangioma endothelial cells (hemECs) and hemangioma tissue is markedly reduced compared to controls. Low VEGFR1/Flt-1 expression in hemECs results in VEGF-dependent activation of VEGFR2/KDR/Flk-1 and downstream signaling pathways. In hemECs, transcription of the gene encoding VEGFR1/Flt-1 (FLT1) is dependent on nuclear factor of activated T cells (NFAT). Low VEGFR1/Flt-1 expression in hemECs is caused by reduced activity of a pathway involving beta1 Integrin, the integrin-like receptor tumor endothelial marker-8 (TEM8), VEGFR2/KDR/Flk-1 and NFAT. In a subset of individuals with hemangioma, we found missense mutations in the genes encoding VEGFR2/KDR/Flk-1 (VEGFR2/KDR/Flk-1) and TEM8 (ANTXR1). These mutations result in increased interactions among VEGFR2/KDR/Flk-1, TEM8 and beta1 Integrin proteins and in inhibition of Integrin activity. Normalization of the constitutive VEGFR2/KDR/Flk-1 signaling in hemECs with soluble VEGFR1/Flt-1 or Antibodies that neutralize VEGF or stimulate beta1 Integrin suggests that local administration of these or similar agents may be effective in hemangioma treatment.