COMP-Ang1 has retinal neuroprotective properties after hypoxic and vascular insults

Abstract

 

Purpose

 

To assess visual functional recovery and retinal structural integrity status post induced vascular accidents in retina treated with COMP-Ang1. Central Retinal Artery Occlusion (CRAO) is the ocular correlate of disorders which lead to cerebral stroke and myocardial infarction; however, no proven medical treatments for CRAO exist. Thus potential neuroprotective therapies are significant. The nervous and vascular systems develop in synchrony and share many receptors and signaling cascades in common, e.g., VEGF/VEGFR2. Angiopoietins represent another family of growth factors that mediate effects in both vascular and nervous systems. Angiopoietin 1 (Ang1) is a growth factor that increases blood vessel stabilization and survival. Additionally, Ang1 has demonstrated neuroprotective effects which act on neuronal cells. In our work, COMP-Ang1 (a more soluble and potent recombinant form of Ang1) has shown to improve neurological deficits by promoting neuronal survival in CRAO via neuroprotection.

 

Methods

 

Mice were pre-treated with AAV2.COMP-Ang1 or control (PBS). After undergoing CRAO, mice were assessed for visual tracking response (OptoMotry). ERG response was taken from a different cohort of mice treated after CRAO with COMP-Ang1 protein or control (PBS) to determine electrical retinal function, in both scotopic and photopic conditions.

 

Results

 

After CRAO, mice treated with COMP-Ang1 experienced greater recovery in visual tracking response compared to controls. In primary studies, diminished ERG responses were ameliorated by treatment with COMP-Ang1.

 

Conclusions

 

We observe that COMP-Ang1 acts directly on retinal ganglion cells to promote survival after CRAO. Our initial data demonstrates a role for COMP-Ang1 in neuroprotection via preventing visual deficits in tracking behavior and electrical response. Our studies show a potential use for COMP-Ang1 in prevention of neuronal damage when administered before CRAO and even when administered shortly after CRAO.

 

 

Normal fundus fluorescein angiography in a mouse retina before (a) and after CRAO in mice treated with PBS (b) or COMP-Ang1 (c). Retinal histology of plastic embedded toluidine blue stained retinas demonstrated cross sectional morphology in control (d), and CRAO mice treated with PBS (e) or COMP-Ang1 (f).

 

Keywords: 695 retinal degenerations: cell biology • 615 neuroprotection • 688 retina