Increased Tie2 expression, enhanced response to angiopoietin-1, and dysregulated angiopoietin-2 expression in hemangioma-derived endothelial cells

Infantile hemangiomas are endothelial tumors that grow rapidly in the first year of life and regress slowly during early childhood. Although hemangiom as are well-known vascular lesions, little is known about the mechanisms th at cause the excessive endothelial cell proliferation in these most common tumors of infancy. To investigate the molecular basis of hemangioma, we iso lated endothelial cells from several proliferative-phase lesions and showed that these cells are clonal and exhibit abnormal properties in vitro (E. B oye, Y. Yu, G. Paranya, J. B. Mulliken, B. R. Olsen, J. Bischoff: Clonality and altered behavior of endothelial cells from hemangiomas. J Clin invest 2001, 107:745-752). Here, we analyzed mRNA expression patterns of genes req uired for angiogenesis, including members of the vascular endothelial growt h factor (VEGF)/VEGF receptor family and the angiopoietin/Tie family, in he mangioma-derived and normal endothelial cells. KDR, Flt-1, Tie1, Tie2, and angiopoietin-2 (Ang2) were strongly expressed in cultured hemangioma-derive d endothelial cells and in hemangioma tissue. In contrast, there was little expression of angiopoietin-1 (Ang1) or VEGF. We found Tie2 mRNA and protei n up-regulated with a concomitant increase in cellular responsiveness to An g1 in most hemangioma-derived endothelial cells. Ang2 mRNA was down-regulat ed in response to serum in hemangioma-derived endothelial cells, but not in normal endothelial cells, suggesting altered regulation. These findings im plicate Tie2 and its ligands Ang1 and Ang2 in the pathogenesis of hemangiom a.