Complexities in the relationship between aqueous and vitreous VEGF revealed by mathematical models fit to meta-analytic data

Abstract

Purpose : Many studies measure aqueous VEGF concentration as a proxy for vitreous VEGF concentration. Usually, underlying these studies is the assumption that aqueous VEGF is merely the result of diffusion from the vitreous compartment. Here, we examine the validity of this assumption by implementing it into a mathematical model and assessing how well it fits real data compared to models which implement additional potential mechanisms of intraocular VEGF production and transport.

Methods : This study consists of a meta-analysis of prior studies followed by the generation and fitting of mathematical models to pooled study data. More specifically, a search of studies that simultaneously report both aqueous VEGF and vitreous VEGF concentrations was conducted, and the data was compiled to determine the relationship between the two concentrations and how their corresponding ratio varies with increasing concentration. Several mathematical models, each representing a different potential mechanism of VEGF production or transport, were then generated and fit to the data, and the resulting coefficients of determination (R² values) were compared.

Results : As Fig 1 shows, the base model, which only considers the production and subsequent diffusion of vitreous VEGF to the aqueous compartment, where it undergoes clearance, fit the meta-analysis data poorly (average R² = 0.162). Models which implemented additional mechanisms on top of the base model performed better (average R² values ranging from 0.463 to 0.707), with a model exhibiting supplementary VEGF production in the aqueous compartment or by the ciliary body performing best (average R² = 0.707).

Conclusions : The base model is insufficient to explain the relationship between aqueous and vitreous VEGF concentrations. Other mechanisms of VEGF production and/or transport must be present, with a strong candidate being the addition of VEGF production in the aqueous compartment or by the ciliary body.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

 

Fig 1. Fitting of mathematical models to pooled study data. (A) Diagram of the eye and the mechanisms of VEGF production, transfer, and clearance that were modeled. (B-E) Fitting of the base mode (model 0) (B, C) and the best performing model (model 3) (D, E) to the pooled study data of aqueous VEGF vs. vitreous VEGF concentration (B, D) and vitreous:aqueous VEGF ratio vs. vitreous VEGF concentration (C, E). (F) Average R² value for each model.