Vegf's Longitudinal Effect on the Retina and Retinal Vasculature in Vivo

Mitton, Kenneth

Abstract

VEGF-blocking therapy is used to treat neovascular proliferation and retinal edema in AMD and diabetic retinopathy. VEGF affects many processes, including: angiogenesis, vascular homeostasis, neovascularization, inflammatory response and disruption of the blood retinal barrier. Furthermore, several isoforms of VEGFA may drive either neovascularization or retinal edema (leaky blood vessels). VEGF-blocking drugs injected into the eye can enter the circulation and drop serum levels of VEGFA. Also, the safety of using VEGF-blockers for retinopathy of prematurity is unclear because treatment could block normal vessel growth. Thus, it is important to understand the mechanisms of VEGFA's action in the retina. Gaps remain in our knowledge because most investigations do not differentiate between the different isoforms of VEGFA. VEGFA-165 is an isoform that drives neovascular retinal disease. Recently, so-called anti- angiogenic b-isoforms of VEGFA were discovered including VEGFA-165b. There are suggestions that VEGFA-165b might be used therapeutically to counter retinal the neovascularization, but we don't know if VEGFA-165b causes vascular leakage like its regular isoform. We hypothesize that VEGFA-165b can still disrupt the blood retinal barrier and cause inflammation, regardless of its anti-angiogenic activity. In fact our preliminary data indicate this is so. To test this hypothesis, and with the involvement of numerous undergraduate students, we developed an intravitreal injection model (rat) to compare the effects of VEGFA-165 and -165b on the retinal vasculature. We will also use cultures of Human Retinal Endothelial Cells to compare the cell-signaling pathways activated by both isoforms in this cell-type. Results will increase our understanding of molecular events triggered by each VEGFA-165 isoform, and provide a model system with future application to study the efficacy and safely of new VEGF-modulating drugs.

Public Health Relevance

Increased Vascular Endothelial Growth Factor A-165 (VEGFA-165) concentration causes the growth of leaky new blood vessels in retinopathy of prematurity, diabetic retinopathy and Age-related Macular Degeneration. A related form called VEGFA-165b is considered a possible therapy to counter to VEGFA-165's growth effects. However, we hypothesize that VEGFA-165b still causes already formed vessels to leak like VEGFA-165, and we have developed a rat-based model and cell-culture model to confirm or disprove this hypothesis and answer this important question.