The Role of Angiopoietins in Neovascular Diabetes-Related Retinal Diseases

Abstract

Diabetic retinopathy is a devastating and frequent complication of poorly controlled diabetes, whose pathogenesis is still only partially understood. Advances in basic research over the last two decades have led to the discovery of angiopoietins, proteins that strongly influence the growth and integrity of blood vessels in many vascular beds, with particular importance in the retina. Angiopoietin 1 (Ang1), produced mostly by pericytes and platelets, and angiopoietin 2 (Ang2), produced mainly by endothelial cells, bind to the same receptor (Tie2), but exert opposing effects on target cells. Ang1 maintains the stability of the mature vasculature, while Ang2 promotes vessel wall destabilization and disruption of the connections between endothelial cells and pericytes. Human retinal endothelial cells exposed to Ang2 show reduced membrane expression of the adhesion molecule VE-cadherin, and patients with proliferative diabetic retinopathy or diabetic macular edema have markedly increased vitreal concentrations of Ang2. Faricimab, a bi-specific antibody simultaneously directed against Ang2 and VEGF, has shown promising results in clinical trials among patients with diabetic retinopathy, and other agents targeting the angiopoietin system are currently in development.

Keywords: Angiopoietins; Diabetes complications; Faricimab; Macular edema; Retinopathy; Tie2.

Fig. 1

A General structure of the Tie2 receptor. The extracellular domain of Tie2 has three Ig-like domains, with an EGF-like domain in between Ig-like domains 2 and 3, and a fibronectin-like type III domain between Ig-like domain 3 and the transmembrane segment. The intracellular domain has tyrosine kinase activity. B General structure of angiopoietins. Angiopoietins 1 and 2 share a structure with an N-terminal superclustering domain (which allows the formation of multimers), a central, coiled-coil domain, and a C-terminal fibrinogen-like domain, which is necessary for receptor binding

Fig. 2

Signaling pathway of the Tie2 receptor. Upon binding of Ang1, the Tie2 receptor is auto-phosphorylated and activated. The activated Tie2 receptor then stimulates a number of intracellular signaling cascades, in particular the phosphoinositide 3-kinase (PI3K) pathway. This pathway leads to activation of the GTPase RAC1 and subsequent inhibition of the GTPase RhoA, via the transducer molecule p190RhoGAP. RAC1 and RhoA then act jointly to induce a reorganization of the cytoskeleton and accumulation of VE-cadherin at adherens junctions. These concerted actions ultimately impede both de novo blood vessel growth and vascular hyperpermeability. Tie2 activation also causes recruitment of ABIN-2 (A20-binding inhibitor of NFkB-2), which suppresses NFkB activity and protects endothelial cells from apoptosis. The protein tyrosine phosphatase VE-PTP acts as a negative regulator of Tie2 signaling

Fig. 3

Scheme of the general structure of faricimab