The Ang/Tie pathway's influence on vessel stability and angiogenesis makes it an interesting vascular target in the treatment of various diseases. Tie2 is a transmembrane receptor that is expressed on endothelial cells. In the retina, under normal circumstances, signaling through the Tie2 receptor has a stabilizing effect on the vasculature, whereas, in disease, Ang2 levels are elevated, inhibiting Tie2, which promotes vascular leak and inflammation.

In the setting of a normal retina (ie, in a quiescent retinal vasculature), Ang1 is expressed constitutively and binds to the Tie2 receptor. This results in a clustering of multiple Tie2 receptors and downstream signaling that causes the junctions between cells to become very tight. In addition, endothelial cells become closely coupled to pericytes and the extracellular matrix, promoting their survival and quiescence, making them less responsive to VEGFA and other vasoactive factors.

However, when the retina becomes hypoxic or ischemic, there is stabilization of hypoxia-inducible factor-1 (HIF-1), which is a master transcription factor that upregulates a large number of genes. Among those genes are those coding for Ang2, VEGFA, and other VEGF family members. In this setting, the increased expression of Ang2 far exceeds the constitutively produced levels of Ang1 and outcompetes Ang1 for binding to the Tie2 receptor. Importantly, when Ang2 binds to Tie2, there is no receptor clustering or downstream signaling, so Ang2 serves as a Tie2 antagonist. 

The absence of Tie2 downstream signaling results in the decoupling of the endothelial cells from the extracellular matrix and pericytes, which makes them more dependent on soluble signals, the major one being VEGFA. VEGF receptor signaling then causes endothelial cell proliferation and loosening of the junctions between the cells, leading to leakage from preexisting vasculature and the development of new vessels that are also leaky. 

The Ang/Tie pathway acts like a rheostat. Under normal circumstances, it is turned "on" and keeps the endothelial cells less responsive to VEGFA and other soluble signals that promote leakage and neovascularization. But, in the setting of hypoxia or ischemia, the rheostat is turned "down" by high levels of Ang2, making cells more responsive to VEGF.

These processes are relevant to all ischemic retinopathies, including proliferative diabetic retinopathy, diabetic macular edema, retinal vein occlusion, and retinopathy of prematurity. The process is similar in the choroid, except that the vessels in the choroid are already fenestrated, but, because of the barrier at the level of the retinal pigment epithelium (RPE), there is no leakage into the retina. In the setting of neovascular age-related macular degeneration, new vessels penetrate through the RPE or cause it to become leaky, causing exudation that is driven by VEGF and facilitated by Ang2. 

So, how does this all relate to inflammation? Tie2 receptors are located primarily on endothelial cells, but they are also on some bone marrow–derived cells. In addition to increasing the responsiveness of endothelial cells to VEGF, Ang2 stimulates the recruitment of bone marrow–derived cells. The combination of Ang2 and VEGF increases the recruitment of cells that normally pass through the retina, resulting in greater numbers of inflammatory cells in the retina. 

Some of the results with faricimab, a recently approved bispecific antibody that inhibits both VEGFA and Ang2, are encouraging. The data indicate that there may be an added benefit to blocking Ang2 in addition to suppressing VEGF. Other approaches that are being studied to modulate or activate the Tie2 pathway include the use of an Ang1-like agonist or the use of an antagonist of vascular endothelial-protein tyrosine phosphatase (VE-PTP). VE-PTP is a protein that is also upregulated by hypoxia and reduces Tie2 signaling by dephosphorylating Tie2. Thus, Tie2 is highly regulated and is stimulated by Ang1, agents that mimic Ang1, or agents that block VE-PTP or Ang2. Blocking Ang 2 allows endogenous Ang1 to stimulate Tie2, while blocking VE-PTP or providing an agent that mimics Ang1 directly stimulates Tie2.