Multiple classes of factors contribute to angiogenesis. In past years, the primary focus has been to understand the functions of individual classes of angiogenic factors. However, few studies have focused on the combinatorial roles of multiple classes of factors in angiogenesis. In this report, we have investigated the in vivo angiogenic processes regulated by two major classes of angiogenic factors, the angiopoietins and vascular endothelial growth factor (VEGF). Here we show that angiopoietin-1, a factor previously considered to be proangiogenic, can offset VEGF-induced angiogenesis in vivo . We also provide direct in vivo evidence for the synergistic effect of angiopoietin-2 and VEGF on the induction of angiogenesis. Furthermore, we show that these two classes of factors control the ratio of arterial and venous blood vessel types during angiogenesis. We believe that our study is a step toward understanding how multiple classes of factors harmonize angiogenesis and blood vessel types.