Article abstract
Nature Medicine 14, 1236 - 1246 (2008)
Published online: 19 October 2008 | doi:10.1038/nm.1877
Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma
Masatoshi Jinnin1, Damian Medici1, Lucy Park1, Nisha Limaye2, Yanqiu Liu1, Elisa Boscolo3, Joyce Bischoff3, Miikka Vikkula2, Eileen Boye1 & Bjorn R Olsen1
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 
1 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 1 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 1 integrin suggests that local administration of these or similar agents may be effective in hemangioma treatment.
- Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, Massachusetts 02115, USA.
- Human Molecular Genetics, de Duve Institute, Avenue Hippocrate 74, Universite Catholique de Louvain, Brussels B-1200, Belgium.
- Vascular Biology Program, Department of Surgery, Children's Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
Correspondence to: Bjorn R Olsen1 e-mail: bjorn_olsen@hms.harvard.edu
Correspondence to: Eileen Boye1 e-mail: eileen_boye@hms.harvard.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
A GTP-binding adapter protein couples TRAIL receptors to apoptosis-inducing proteinsNature Immunology Article (01 Jun 2001)
Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transferNature Immunology Article (01 Oct 2001)
Is the nitric oxide system involved in genetic hypertension in Dahl rats?Kidney International Original Article
Infantile hemangiomas are arrested in an early developmental vascular differentiation stateModern Pathology Original Article
See all 10 matches for Research
