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Updated: Feb 13, 2026
A Mouse Model for Laser-induced Choroidal Neovascularization
Published on: December 27, 2015
A Highly Active Angiopoietin 1 Mimetic Potentiates Angiogenesis in Mouse Models of Choroidal Neovascularization
Asmaa A Youssif1,2,3, Pan Liu1,4, Danille Gaczkowski1,2
1Feinberg Cardiovascular and Renal Research Inst. Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Purpose:
The angiopoietin (ANGPT) pathway, comprised of the ANGPT ligands and their receptor Tie2, mediates angiogenesis and is a compelling target for neovascular age-related macular degeneration (nvAMD). Tie2 phosphorylation by ANGPT1 is associated with vascular stability and may be protective in nvAMD. In contrast, ANGPT2 potentiates angiogenesis and the bispecific ANGPT2/VEGF blocking antibody Faricimab has recently been approved for nvAMD. However, despite clear links between the ANGPT pathway and nvAMD and the success of Faricimab, poor characteristics of existing ANGPT1-based therapies have hindered their adoption as an alternate targeting strategy.
Methods:
Hepta-ANGPT1 is an ANGPT1-mimetic fusion protein with improved activity, solubility, and half-life, addressing limitations of earlier mimetics. Here we used laser-induced and RNV3 (JR5558) models of mouse choroidal neovascularization (CNV) to investigate Hepta-ANGPT1 in CNV and explore its potential as a therapy for nvAMD.
Results:
Hepta-ANGPT1 induced robust Tie2 phosphorylation in the choroid and did not lead to angiogenesis in healthy eyes. However, after laser CNV, we observed increased neovascularization in Hepta-ANGPT1-treated eyes, as well as increased number and size of neovascular lesions in treated RNV3 mice, indicating that Hepta-ANGPT1 potentiated angiogenesis. In contrast, CNV lesion size was smaller in Tie2 knockout mice, and no Hepta-ANGPT1-mediated increase was observed in knockout animals, confirming specificity.
Conclusions:
Although previous studies have found ANGPT1 to be protective in mouse CNV, Tie2 activation is pro-angiogenic in other tissues, including the cornea and iridocorneal angle. Hepta-ANGPT1 induced a similar effect in CNV, suggesting that under certain conditions, Tie2 activation can be detrimental in this disease.
Translational Relevance:
Understanding the contexts under which Tie2 activation is beneficial and where it is harmful will be critical to successful development of new Tie2-activating drugs for nvAMD.
Insights
Hepta-ANGPT1, a novel angiopoietin-1 mimetic, unexpectedly promoted angiogenesis in models of neovascular age-related macular degeneration (nvAMD). Further research is needed to understand Tie2 activation contexts for effective nvAMD therapies.
Area of Science:
- Ophthalmology
- Vascular Biology
- Drug Development
Background:
- The angiopoietin (ANGPT) pathway, including ANGPT1 and its receptor Tie2, plays a critical role in angiogenesis.
- While ANGPT1 is generally associated with vascular stability, its role in neovascular age-related macular degeneration (nvAMD) is complex.
- Existing ANGPT1-based therapies have limitations, hindering their clinical adoption for nvAMD.
Purpose of the Study:
- To evaluate the efficacy of Hepta-ANGPT1, an improved ANGPT1-mimetic fusion protein, as a potential therapy for nvAMD.
- To investigate the effects of Hepta-ANGPT1 on choroidal neovascularization (CNV) in preclinical models.
Main Methods:
- Utilized laser-induced and RNV3 (JR5558) mouse models of CNV.
- Administered Hepta-ANGPT1 and assessed Tie2 phosphorylation, angiogenesis, and neovascular lesion size.
- Included Tie2 knockout mice to confirm specificity.
Main Results:
- Hepta-ANGPT1 induced Tie2 phosphorylation without causing angiogenesis in healthy eyes.
- In CNV models, Hepta-ANGPT1 significantly increased neovascularization and lesion size.
- These pro-angiogenic effects were absent in Tie2 knockout mice, confirming target specificity.
Conclusions:
- Contrary to expectations, Hepta-ANGPT1 demonstrated pro-angiogenic activity in CNV models, suggesting Tie2 activation can be detrimental in nvAMD under certain conditions.
- Understanding the context-dependent effects of Tie2 activation is crucial for developing effective nvAMD therapies.
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