Angiopoietin-2 (Ang2) is a protein that plays a significant role in the regulation of blood vessels throughout the body. Its involvement in both normal bodily functions and various disease processes makes it a subject of ongoing investigation in medicine.
The Angiopoietin System and Ang2’s Role
Angiopoietin-2 (Ang2) is a member of the angiopoietin family of growth factors, involved in blood vessel formation and stability. This family primarily interacts with a specific receptor on endothelial cells, the cells that line blood vessels, known as Tie2. The core components of this system are Angiopoietin-1 (Ang1) and Ang2, which both bind to the Tie2 receptor but often have contrasting effects.
Ang1 acts as an activating ligand for Tie2, promoting the maturation and stabilization of blood vessels. It helps recruit pericytes, supportive cells that wrap around blood vessels, tightening cell junctions and maintaining vascular wall integrity, thereby reducing permeability. In healthy individuals, Ang1 levels remain sustained, contributing to stable vasculature and suppressing inflammation.
In contrast, Ang2, primarily produced by endothelial cells, acts as a competitive antagonist to Ang1, blocking Ang1’s stabilizing effects on Tie2. When Ang2 binds to Tie2, it can lead to blood vessel destabilization, promoting pericyte detachment and loosening cell junctions, which increases vascular permeability. This destabilization can pave the way for new blood vessel sprouting, known as angiogenesis, particularly when other pro-angiogenic factors like Vascular Endothelial Growth Factor (VEGF) are present.
Ang2’s Involvement in Disease
Elevated Ang2 levels are a characteristic feature of numerous pathological conditions, contributing to disease progression. In cancer, Ang2 plays a significant role in tumor angiogenesis, the formation of new blood vessels that supply tumors with nutrients and oxygen, and metastasis, the spread of cancer cells. Hypoxia, a state of low oxygen, and certain cytokines, signaling molecules involved in inflammation, can induce Ang2 expression in endothelial cells, promoting tumor progression. Ang2 can also interact with tumor cells and myeloid cells, attracting them into tumors and promoting their pro-tumor activity.
Ang2 is also implicated in a range of inflammatory diseases, including sepsis, acute respiratory distress syndrome (ARDS), and inflammatory bowel disease. In these conditions, increased Ang2 acts on endothelial cells, enhancing vascular permeability and causing pericyte detachment from the basement membrane. This leads to increased leakage from blood vessels and facilitates the trans-endothelial migration of immune cells, exacerbating inflammation and tissue damage. Higher Ang2 levels have been associated with increased mortality in conditions like cardiogenic shock following myocardial infarction.
Ang2 contributes to the progression of several eye diseases, such as diabetic retinopathy and age-related macular degeneration (AMD). In diabetic retinopathy, patients with the proliferative form or diabetic macular edema often exhibit high concentrations of Ang2 in the vitreous, the gel-like substance filling the eye. In exudative AMD, increased Ang2 expression contributes to the abnormal formation of new, leaky blood vessels in the choroid, leading to vision loss. By promoting leaky vessels and abnormal angiogenesis, Ang2 directly contributes to the severity and progression of these eye conditions.
Targeting Ang2 for Treatment
Understanding Ang2’s involvement in disease has led to the exploration of therapeutic strategies aimed at modulating its activity. One primary approach involves directly blocking Ang2 to inhibit its destabilizing effects on blood vessels. Drugs designed to neutralize Ang2 work by preventing its interaction with the Tie2 receptor, thereby reducing abnormal angiogenesis and vascular leakage.
Another strategy focuses on enhancing Angiopoietin-1 (Ang1) signaling through the Tie2 receptor, which promotes vascular stability and maturation. While Ang1 is considered protective, its levels can be low or decreased in certain diseases, making its enhancement a potential therapeutic avenue. Some experimental approaches use antibodies that not only block Ang2 but also activate Tie2 signaling, aiming for a dual benefit of reducing destabilization while promoting stability.
Several Ang2-targeting drugs are currently in clinical trials for various conditions. For instance, faricimab is a bispecific antibody that targets both Ang2 and VEGF, another pro-angiogenic factor, showing promising results in retinal diseases like diabetic retinopathy and wet AMD. MEDI3617, a selective Ang2 inhibitor, has shown to inhibit angiogenesis and tumor growth in preclinical models and is being investigated in phase I clinical trials for advanced solid tumors, often in combination with chemotherapy.