Tie2 is present in phosphorylated form in quiescent and activated ECs throughout the body [62] . Signalling is initiated by autophosphorylation of Tie2 after Ang-1 binding and is conducted by several distinct pathways [54, 71, 79, 80] . Tie2 can also be activated at cell-cell contacts when Ang-1 induces Tie2/Tie2 homotypic intercellular bridges [65] . In human umbilical vein endothelial cells (HUVECs), Ang/Tie signalling resulted in 86 upregulated genes and 49 downregulated genes [81, 82] . Akt phosphorylation by PI3K with interaction of nitric oxide is the most important intracellular pathway [51, [83] [84] [85] [86] ; however, ERK1/2, p38MAPK, and SAPK/JNK can also participate in Ang/Tie downstream signalling [71, 81, 84, [87] [88] [89] [90] . Endothelial barrier control by Ang-1 requires p190RhoGAP, a GTPase regulator that can modify the cytoskeleton [80] . The transcription factors FOXO1, activator protein-1, and NF-κ B are involved in Ang/Tie-regulated gene transcription [75, [91] [92] [93] . Ang-1induced signalling is has also been implicated in cell migration induced by reactive oxygen species [94] . ABIN-2 (A20-binding inhibitor of NF-κB 2), an inhibitor of NF-κB, is involved in Ang-1-regulated inhibition of endothelial apoptosis and inflammation in HUVECs [93] . However, the downstream signalling of Tie2 varies depending on cell type and localization and whether a cell-cell or cell-matrix interaction in involved, which results in spatiotemporally different patterns of gene expression. For example, Ang-1/Tie2 signalling leads to Akt activation within the context of cell-cell interaction, but it leads to ERK activation in the context of cell-matrix interaction. The microenvironment of the receptor in the cell membrane plays a central role in this signal differentiation. Adaptor molecules such as DOK and SHP2 and the availability of substrate determine which protein is phosphorylated [95] .