After binding of Ang-1, and to a lesser extent Ang-2, Tie2 is internalized and degraded, and Ang-1 is shed in a reusable form [50] . VEGF is an important co-factor that can exert different effects on Ang-1 and Ang-2 signalling [88] . Ang-2 is antiapoptotic in the presence of VEGF but induces EC apoptosis in its absence [96] . Autophosphorylation and subsequent signalling are inhibited by heteropolymerization of Tie1 and Tie2 [59] . Although the Ang/Tie system appears to play its role mainly in paracrine and autocrine processes, its circulating components have been found in plasma. The significance of this finding in health and disease has yet to be determined.