Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma.
Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma.
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婴儿血管瘤是局部和快速生长的区域紊乱的血管生成。我们证明血管瘤内皮细胞（hemEC）和组织中VEGF 1的表达仅为对照组的10 - 20%。低VEGFR 1水平导致VEGFR 2和下游通路的VEGF依赖性激活。我们发现，VEGFR 1的转录是NFAT依赖性的，并且hemEC中VEGFR 1的低表达是由β1整联蛋白、整联蛋白样受体TEM 8、VEGFR 2和NFAT的通路的活性降低引起的。在血管瘤患者的一个子集中，我们发现VEGFR 2或TEM 8的错义突变。进一步的研究表明，突变导致VEGFR 2、TEM 8和β1整联蛋白之间的相互作用增加，并抑制整联蛋白活性。用可溶性VEGFR 1和阻断VEGF或刺激β1整联蛋白的抗体使hemEC中的组成性VEGFR 2信号传导正常化，表明局部施用这些或类似药剂可能在血管瘤治疗中有效。
Infantile hemangiomas are localized and rapidly growing regions of disorganized angiogenesis. We demonstrate that expression of VEGFR1 in hemangioma endothelial cells (hemEC) and tissue is only 10−20% of that in controls. Low VEGFR1 levels result in VEGF-dependent activation of VEGFR2 and downstream pathways. We show that VEGFR1 transcription is NFAT-dependent, and that low VEGFR1 expression in hemEC is caused by reduced activity of a pathway involving β1 integrin, the integrin-like receptor TEM8, VEGFR2 and NFAT. In a subset of individuals with hemangioma, we find missense mutations in VEGFR2 or TEM8. Further studies indicate that the mutations result in increased interaction between VEGFR2, TEM8 and β1 integrin and inhibition of integrin activity. Normalization of the constitutive VEGFR2-signaling in hemEC with soluble VEGFR1 and antibodies that block VEGF or stimulate β1 integrin suggests that local administration of these or similar agents may be effective in hemangioma treatment.