Angiopoietins and Their Receptors

Abstract

The angiopoietins (ANG) represent a set of proteins involved in various aspects of angiogenesis and vascular permeability. While several ANG and ANG-like proteins exist ANG1 and ANG2 are the two that have been most studied. Both proteins interact in varying degrees to the TIE2 receptor. In concert with the ligand-less TIE1 receptor the ANG-TIE2-TIE1 complex effects are primarily in vessel maturation and stabilization. This appears to occur in endothelial cells at the junction between neighboring endothelial cells. Additionally, activation of TIE2 also results in Akt activation with its subsequent effects on endothelial cell survival. While the receptors appear to be expressed primarily in endothelial cells they are also found in circulating macrophages. ANG1 appears to be the predominate agonist of the receptor. ANG2, on the other hand, acts as an antagonist and appears to act as a dominant negative by inhibiting binding of ANG1. Various proangiogenic stimuli appear to upregulate ANG2. These include hypoxia, inflammation and vascular endothelial growth factor (VEGF). In addition, exposure to ANG2 typically results in angiogenesis and an increase in vascular permeability. However, the exact relationship between ANG1 and ANG2 in regards to the TIE2 receptor has been shown to be more complex. Under certain conditions ANG2 can act as a mild agonist of the TIE2 receptor. Interestingly ANG2 also plays a concomitant role in VEGF activity. For example, in the absence of ANG2 VEGF activity is attenuated. This aspect has also been demonstrated in various animal models when further studying dual VEGF and ANG2 inhibition. Dual inhibition appears to be superior to anti-VEGF therapy alone in various aspects in animals of human disease. For example, the duration of leakage in animal models of choroidal neovascularization (CNV) or control of ocular inflammation is improved with dual inhibition. The clinical role of the ANG proteins is under active investigation especially as it relates to choroidal neovascularization (CNV) and diabetic retinopathy (DR). Here too some degree of complexity has been observed. In some cases, human vitreous levels of the both ANG1 and ANG2 do not consistently parallel the level of DR. As such the importance and role of the ANG1/ANG2 ratio is unclear. Clinical trials examining the role of dual inhibition using the bispecific antibody faricimab demonstrated that dual inhibition of both ANG2 and VEGF in diabetic macular edema (DME) was superior to anti-VEGF treatment alone in reducing retinal leakage. Similarly dual inhibition appears to result in a more durable anti-permeability effect on CNV in patients than anti-VEGF treatment alone. However, in both cases no evidence of improvements in visual acuity with faricimab were noted. On-going clinical work will further elucidate potential non-endothelial dependent benefits of TIE2 activation. As the TIE2 receptor appears to be involved in maintaining a non-angiogenic, nonfibrotic M1 phenotype in macrophages the role of manipulated ANG2 and ocular fibrosis is the center of continuing research. In summary ANG proteins and their receptors are both critical and complex agents in the pathogenesis of angiogenic diseases.