By Pete Lollar, MD

2009-05-01

Dr. Lollar indicated no relevant conflicts of interest.

Jinnin M, Medici D, Park L, et al. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat Med. 2008;14:1236-46.

Infantile hemangiomas are the most common tumors of infancy. They typically proliferate during the first year of life and involute during the first decade. Hemangiomas are characterized by disorganized vascular growth and the clonal proliferation of hemangioma endothelial cells (hemECs). They may require therapeutic intervention if they are large or compromise eating, breathing, or other functions. Glucocorticoids are effective in some, but not all, cases.

Jinnin, et al., from Bjorn Olsen’s lab at Harvard, compared cultured hemECs from nine infantile hemangioma patients to cultured human dermal microvascular endothelial cells (HDMECs) from normal individuals. They found that expression of vascular endothelial growth factor receptor-1 (VEGFR1) in hemECs was decreased compared to HDMECs. VEGFR1 is a decoy receptor that competes for binding of VEGF to VEGFR2. The resulting low VEGFR1 expression in hemECs results in increased VEGFR2 expression (see Figure). Activation of downstream VEGFR2 signaling pathways results in increased expression of VEGF, the glucose transporter GLUT-1, and several phosphorylated proteins, including phospho-ERK and phospho-Akt. Constitutive VEGFR2 signaling in hemECs was decreased by soluble VEGFR1 or antibodies that neutralize VEGF or stimulate β1 integrin.

The authors identified a putative promoter for the transcription factor, nuclear factor of activated T cells (NFAT), in the gene encoding VEGFR1 (FLT1) and found that transcription of FLT1 in HDMECs was NFAT-dependent. The expression of NFAT and several of its target genes, including FLT1 and the gene for cycloxygenase-2 (PTSG2), was decreased in hemECs. NFAT is a known target of VEGFR2 signaling in endothelial cells. Because VEGFR2 signaling is up-regulated in hemECs, the finding of decreased NFAT activity was unexpected.

Further investigation using the clue that NFAT activation and integrin signaling are both Ca2+-dependent led to the identification of β1 integrin as an NFAT activator. Immunoprecipitation experiments revealed that the integrin-like receptor tumor endothelial marker-8 (TEM8), VEGFR2, and β1 integrin form a complex on the surface of HDMECs and hemECs. Sequencing of 24 candidate genes led to the identification of missense mutations in genes encoding VEGFR2 (KDR) or TEM8 (ANTXR1, the anthrax receptor) in three of the nine patients. Experiments involving heterologous expression of wild-type and mutant genes in hemECs and HDMECs, respectively, revealed an increased interaction between VEGFR2, TEM8, and β1 integrin in hemECs. However, in hemECs, β1 integrin is present in an inactive state, apparently accounting for the anomalous decrease in activated NFAT.

The study by Jinnin, et al. is important because it provides a mechanistic model that describes the development of hemangiomas. The central feature of the model is imbalanced expression between the decoy receptor, VEGFR1, and VEGFR2 and their interrelated signaling pathways (see Figure). The model accounts for previously described molecular changes in hemangiomas, such as increased expression of GLUT1, which has been used to differentiate hemangiomas from other vascular lesions. Further analysis of the VEGFR1 and VEGFR2 pathways may reveal additional insights into the pathophysiology of the growth and involution of hemangiomas. Also, additional genetic abnormalities that contribute to the development of hemangiomas may be discovered. The finding that VEGFR1/VEGFR2 balance can be modified by extracellular ligands suggests a novel therapeutic approach to the treatment of hemangiomas. Bevacizumab, an anti-VEGF antibody that is approved by the FDA for the treatment of metastatic cancer, is a potential candidate.

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