Angiogenesis, a process of blood vessel formation whereby new vessels sprout and mature from the preexisting vasculature, is required for a variety of physiologic processes, including pregnancy, wound healing, tissue repair, and organ regeneration. Angiogenesis also contributes to the development of pathologic conditions such as cancer progression and metastasis, diabetic retinopathy, psoriasis, atherosclerosis, and rheumatoid arthritis. [2,3]
Angiogenesis is a complicated process that is regulated by numerous factors that occur simultaneously and in a coordinated fashion. The process of angiogenesis requires that endothelial cells (ECs) detach from pericytes and the extracellular matrix (ECM), proliferate, migrate, and form capillary tubes that connect to other newly developed vascular tubes. The result is a primitive yet functional vascular network. Recent evidence indicates that the presence of specific cytokines mediates EC "stability/instability."  These factors either protect EC from undergoing apoptosis or facilitate EC "instability" that allows the response to mitogenic factors. The angiopoietins are a family of proteins that mediate EC stability and survival. A better understanding of the biologic effects of angiopoietins in the angiogenic process may contribute to the development of novel therapeutic strategies.
The angiopoietins are a family of growth factors identified as being specific for the vascular endothelium. The specificity of the angiopoietins for the vascular endothelium results from the restricted distribution of the angiopoietin tyrosine kinase receptor Tie-2 (also known as TEK ) to endothelial cells. Four different angiopoietinsAng-1 through Ang-4have been described.[7-9] The best characterized of these are Ang-1 and Ang-2. Ang-1 exerts its biologic effect by binding to Tie-2, inducing phosphorylation of Tie-2.[10,11] Ang-1 also may control the ability of ECs to stabilize the structure and modulate the function of blood vessels. In vivo analysis by targeted gene inactivation revealed that Ang-1 recruits and sustains periendothelial support cells. Ang-2 is antagonistic to Ang-1 and also binds to Tie-2, but it does not typically induce phosphorylation. However, at supraphysiologic doses, Ang-2 also may initiate EC signaling and survival. Tie-1 is an orphan receptor, but its ligand has not been identified.
Several investigators have demonstrated in vitro that Ang-1 serves as a survival factor for ECs. Kwak and associates  examined the effect of Ang-1 on apoptosis in human umbilical vein ECs (HUVECs). Ang-1 dose-dependently inhibited apoptosis under serum-deprived conditions, with significant inhibition occurring with Ang-1 doses as low as 50 ng/mL. Furthermore, the addition of 20 ng/mL VEGF (a potent angiogenic factor known also to be an EC survival factor) to 200 ng/mL Ang-1 augmented the antiapoptotic effects of Ang-1, suggesting that Ang-1 acted in conjunction with VEGF.
Similar results were obtained by Papapetropoulos et al, who also demonstrated dose-dependent stabilization of HUVEC network organization by Ang-1. In addition, these authors demonstrated that this response was indeed dependent on Tie-2 activation, as addition of a soluble form of Tie-2, but not Tie-1, completely blocked the effects of Ang-1. It was also demonstrated that the signaling pathway by which Ang-1 protects ECs from apoptosis is likely through phosphorylation of the survival serine-threonine kinase, Akt. [16,17] This finding occurred in association with the up-regulation of the apoptosis inhibitor, survivin, in ECs and protection of endothelium from apoptosis. In addition, transfection of a dominant-negative survivin construct abrogated the ability of Ang-1 to protect cells from undergoing apoptosis. These data suggest that the activation of antiapoptotic pathways mediated by Akt and survivin in ECs may contribute to Ang-1 stabilization of vascular structures during angiogenesis.
It is likely that Ang-1 works in conjunction with VEGF to help stabilize vascular networks. Ang-1 appears to recruit periendothelial support cells,  and this interaction may be required for EC survival. This is supported by evidence showing that Ang-1 knockout embryos are able to undergo VEGF-dependent angiogenesis, but ECs are unable subsequently to interact with periendothelial support cells. This deficit leads to vascular regression. Ang-2 is antagonistic to Ang-1 and thus leads to EC destabilization. In the presence of VEGF, this destabilization leads to robust angiogenesis.
Inhibition of the activity of the Angs by soluble Tie-2 has been investigated as a method of inhibiting angiogenesis. Lin and colleagues[19,20] constructed an adenoviral vector containing the mouse extracellular domain coding region of Tie-2, which can systemically deliver recombinant soluble Tie-2 (AdExTek) capable of blocking Tie-2 activation. Administration of soluble Tie-2 (AdExTek) inhibited the growth in both primary and metastatic tumors in mice. However, it is unclear whether the observed effects are due to sequestration of Ang-1 or Ang-2.