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

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Abstract
Bjorn Olsen and his coworkers shed light on the molecular mechanisms underpinning the proangiogenic properties of endothelial cells in hemangiomas, tracing these properties to decreased activity of a signaling pathway involving NFAT transcription factor regulation of VEGFR1 receptor expression. They also identify germline mutations in genes encoding elements of this signaling pathway in a subset of individuals with hemangioma and suggest that interventions in this pathway could have therapeutic effects ( pages 1147–1148 ). Infantile hemangiomas are localized and rapidly growing regions of disorganized angiogenesis. We show that expression of vascular endothelial growth factor receptor-1 (VEGFR1) in hemangioma endothelial cells (hemECs) and hemangioma tissue is markedly reduced compared to controls. Low VEGFR1 expression in hemECs results in VEGF-dependent activation of VEGFR2 and downstream signaling pathways. In hemECs, transcription of the gene encoding VEGFR1 (FLT1) is dependent on nuclear factor of activated T cells (NFAT). Low VEGFR1 expression in hemECs is caused by reduced activity of a pathway involving β1 integrin, the integrin-like receptor tumor endothelial marker-8 (TEM8), VEGFR2 and NFAT. In a subset of individuals with hemangioma, we found missense mutations in the genes encoding VEGFR2 (KDR) and TEM8 (ANTXR1). These mutations result in increased interactions among VEGFR2, TEM8 and β1 integrin proteins and in inhibition of integrin activity. Normalization of the constitutive VEGFR2 signaling in hemECs with soluble VEGFR1 or antibodies that neutralize VEGF or stimulate β1 integrin suggests that local administration of these or similar agents may be effective in hemangioma treatment.

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