Ang-2: Branching Out in Retinal Conditions

Following the Science Beyond VEGF

For people with retinal conditions that can cause blindness, the enemy is often uncontrolled blood vessel growth - a process called angiogenesis. This vessel growth can gradually interfere with the eye’s ability to detect light and see clearly. If untreated, this can lead to significant vision loss or blindness in conditions that include neovascular or “wet” age-related macular degeneration (nAMD), diabetic retinopathy (DR) and diabetic macular edema (DME).

The underlying causes of this leakage and vessel branching are still not fully understood. But as scientists uncover more about the biology of blood vessel regulation and development, the hope is that we can develop better approaches towards eye conditions building off of the knowledge we have gained from all the groundbreaking research in ophthalmology to date.

Currently, treatment for retinal conditions revolves around blocking the action of a protein called vascular endothelial growth factor (VEGF), which is one of the master switches for promoting the growth, migration and survival of cells involved in blood vessel construction.

But in a complex biological system, even a master switch cannot control everything. Although medicines that block VEGF have dramatically improved the prognosis for retinal conditions, in some cases reducing the rates of blindness by 75%,1,2 we are studying new targets and approaches with the goal to help the subset of patients who do not respond sufficiently to available medicines. One potential target is the angiopoietin/Tie2 pathway, a complex molecular system that decreases stability and drives the breakdown of existing blood vessel walls.

Angiopoietin-2: A Novel Target

The angiopoietins Ang-1 and Ang-2 regulate blood vessel stability when bound to the Tie2 receptor on the surface of the endothelial cells lining the walls of blood vessels. Under healthy conditions, Ang-1 binds to the Tie2 receptor and helps maintain vessel stability. In doing so, the Ang-1/Tie2 complex essentially acts as a molecular brake that prevents the permeability, leakage and inflammation that are precursors to retinal conditions.

In the eye, Ang-1 binding to Tie2 helps maintain blood vessel stability, while Ang-2 leads to destabilization.

When this process goes awry, Ang-2 releases this molecular brake by overproducing and competitively binding to Tie2, instead. This can occur in response to low oxygen, inflammation or high blood sugar levels associated with diabetes. This change in conditions sets off a cascade of events that leads to the death of cells called pericytes, which help to hold together endothelial cells in blood vessels.

When pericytes die off, it can create increased permeability as the junctures between the cells grow and separate. Increased Ang-2 binding to Tie2 also triggers a flood of inflammatory molecules and cells that prime blood vessels to increase VEGF production and binding. VEGF in turn promotes new branches and vessel extensions resulting in eventual fluid leakage as they push through the retina.

Ang-2 and Tie2 binding, along with VEGF, leads to unstable, leaky blood vessel growth in the eye that can cause vision loss.

Researchers have found elevated levels of both Ang-2 and VEGF in the eyes of people with diabetes and in models for retinal conditions like nAMD, DR and DME. This potential link to the angiopoietin/Tie2 pathway suggests that we need to further understand the impact of blocking Ang-2 simultaneously with VEGF on retinal conditions. Blocking Ang-2 would allow Ang-1 to bind to the Tie2 receptor, which may reinstate vessel stability and reduce inflammation that primes VEGF. Blocking VEGF would then reduce additional vascular leakage by inhibiting new vessel growth. Researchers are studying to see if this synergistic impact may prove to be effective for those patients that do not respond adequately to existing treatments alone.

As our scientists unlock the potential of the Ang/Tie2 pathway, we continue to explore other pathways that play a role in retinal disease. With each experiment and every step forward, we hope to move toward eliminating another common cause of vision loss.

At the frontier of retinal blood vessel research, Ang-2 is one of several new potential targets we are exploring with the goal to improve outcomes for people with retinal conditions.