Identification of angiogenic properties of insulin-like growth factor II in in vitro angiogenesis models

Insulin-like growth factor II (IGF-II), highly expressed in a number of hum an tumours, has been recently known to promote neovascularization in vivo. Yet, the detailed mechanism by which IGF-II induces angiogenesis has not be en well defined. In the present study, we explored an angiogenic activity o f IGF-II in in vitro angiogenesis model. Human umbilical vein endothelial c ells (HUVECs) treated with IGF-II rapidly aligned and formed a capillary-li ke network on Matrigel. In chemotaxis assay, IGF-II remarkably increased mi gration of HUVECs. A rapid and transient activation of p38 mitogen-activate d protein kinase (p38 MAPK) and p125 focal adhesion kinase (p125(FAK)) phos phorylation was detected in HUVECs exposed to IGF-II. IGF-II also stimulate d invasion of HUVECs through a polycarbonate filter coated with Matrigel. Q uantitative gelatin-based zymography identified that matrix metalloproteina se-2 (MMP-2) activity generated from HUVECs was increased by IGF-II. This i nduction of MMP-2 activity was correlated with Northern blot analysis, show ing in HUVECs that IGF-II increased the expression of MMP-2 mRNA, while it did not affect that of TIMP-2, a tissue inhibitor of MMP-2. These results p rovide the evidence that IGF-II directly induces angiogenesis by stimulatin g migration and morphological differentiation of endothelial cells, and sug gest that IGF-II may play a crucial role in the progression of tumorigenesi s by promoting the deleterious neovascularization. (C) 2000 Cancer Research Campaign.