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

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Jinnin, Masatoshi Medici, Damian Park, Lucy Limaye, Nisha [UCL] Liu, Yanqiu Vikkula, Miikka [UCL] Olsen, Bjorn R

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 beta1 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 beta1 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 beta1 integrin suggests that local administration of these or similar agents may be effective in hemangioma treatment.

Document type Article de périodique (Journal article) – Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Access type Accès libre
Publication date 2008
Journal information "Nature medicine" - Vol. 14, no. 11, p. 1236-46 (2008)
Peer reviewed yes
issn 1078-8956
e-issn 1546-170X
Publication status Publié
Affiliation UCL - MD/BICL - Département de biochimie et de biologie cellulaire
MESH Subject Base Sequence ; Cell Proliferation ; Cells, Cultured ; Down-Regulation ; Endothelial Cells - enzymology ; Female ; Hemangioma - genetics - metabolism - pathology ; Humans ; Infant ; Integrin beta Chains - metabolism ; Mutation - genetics ; NFATC Transcription Factors - genetics - metabolism ; Neoplasm Proteins - genetics - metabolism ; Phosphorylation ; Protein Binding ; Receptors, Cell Surface - genetics - metabolism ; Signal Transduction ; Up-Regulation ; Vascular Endothelial Growth Factor Receptor-1 - genetics - metabolism ; Vascular Endothelial Growth Factor Receptor-2 - genetics - metabolism
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Bibliographic reference Jinnin, Masatoshi ; Medici, Damian ; Park, Lucy ; Limaye, Nisha ; Liu, Yanqiu ; et. al. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma.. In: Nature medicine, Vol. 14, no. 11, p. 1236-46 (2008)
Permanent URL http://hdl.handle.net/2078.1/27091