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Sprouting of new capillaries from pre-existing blood vessels is a hallmark of angiogenesis during embryonic development and solid tumor growth [1]. In addition to the vascular endothelial growth factor (VEGF) and its receptors, the Tie receptors and their newly identified ligands, the angiopoietins, have been implicated in the control of blood vessel formation [2,3]. Although 'knockouts' of the gene encoding the Tie2 receptor, or its activating ligand angiopoietin-1 (Ang1), result in embryonic lethality in mice due to an absence of remodeling and sprouting of blood vessels [4,5], biological activity in vitro has not yet been described for this receptor-ligand system. In an assay in which a monolayer of endothelial cells were cultured on microcarrier beads and embedded in three-dimensional fibrin gels, recombinant Ang1 (0.5-10 nM) induced the formation of capillary sprouts in a dose-dependent manner that was completely inhibited by soluble Tie2 receptor extracellular domains. In contrast with VEGF, which also induced sprouting of capillaries, Ang1 was only very weakly mitogenic for endothelial cells. Suboptimal concentrations of VEGF and Ang1 acted synergistically to induce sprout formation. Thus, the biological activity of Ang1 in vitro is consistent with the specific phenotype of mice deficient in Tie2 or Ang1. The data suggest that, like in other developmental systems, blood vessel formation requires a hierarchy of master-control genes in which VEGF and angiopoietins, along with their receptors, are amongst the most important regulators.

The first vasculogenic formation of a primitive embryonic vascular plexus occurs by in situ differentiation of angioblasts. Vasculogenesis is followed by angiogenesis, the sprouting and subsequent remodeling from a pre-existing vasculature. The vasculature in the adult is quiescent with a very low turnover rate of the lining endothelial cell layer with a physiological proliferative turnover within months to years (1, 2). However, it can rapidly respond to angiogenic stimuli supporting a complex morphogenic program that leads to vascular remodeling and induction of neo-angiogenesis. The balance between neovessel formation and homeostasis of the resting vasculature is maintained by a finely tuned balance of proangiogenic and antiangiogenic mediators. The Tie/angiopoietin receptor ligand system is critically involved in regulating both processes, maintaining vascular homeostasis and vessel maturation as well as vascular destabilization and remodeling (1, 3).Two members of the Tie-receptor family with strong sequence homology, Tie-1 and Tie-2, have been identified so far. Both molecules are preferentially expressed by endothelial cells and were originally isolated as orphan receptors (4). They are composed of three EGF 1 homology repeats flanked by two Ig-like loops. The second Ig-like loop is followed by a fibronectin type III domain adjacent to the transmembrane domain. The intracellular domain contains a split tyrosine kinase domain (Fig.

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