Title:
cellular and molecular basis of hemangioma

Masatoshi Jinnin
Associate Professor
Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University

Abstract:
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.

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