# Caffeine Mitigates Adenosine-Mediated Angiogenic Properties of Choroidal Endothelial Cells Through Antagonism of A1 Adenosine Receptor and PI3K-AKT Axis

## TL;DR

Caffeine reduces harmful blood vessel growth in the eye by blocking specific receptors and signaling pathways, offering a potential new treatment for a severe form of age-related macular degeneration.

## Contribution

The study identifies caffeine's antagonism of the A1 adenosine receptor and modulation of the PI3K-AKT axis as key mechanisms for its anti-angiogenic effects in choroidal endothelial cells.

## Key findings

- Caffeine suppresses choroidal neovascularization primarily by antagonizing the A1 adenosine receptor.
- Caffeine's modulation of intracellular cAMP through other adenosine receptors contributes to its anti-angiogenic effects.
- Systemic caffeine administration reduces CNV in vivo, partially mimicked by the A2A antagonist Istradefylline.

## Abstract

What are the main findings?
Antagonism of the A1 adenosine receptor by caffeine is a major mechanism underlying the attenuation of choroidal neovascularization.Modulation of intracellular cAMP levels through the engagement of other adenosine receptors also contributes to the anti-angiogenic effects of caffeine.

Antagonism of the A1 adenosine receptor by caffeine is a major mechanism underlying the attenuation of choroidal neovascularization.

Modulation of intracellular cAMP levels through the engagement of other adenosine receptors also contributes to the anti-angiogenic effects of caffeine.

What are the implications of the main findings?
Targeting the A1 adenosine receptor represents a potential therapeutic strategy to limit choroidal neovascularization.The concurrent antagonism or modulation of other adenosine receptors may provide additional benefit and enhance the efficacy of approaches aimed at suppressing choroidal neovascularization.

Targeting the A1 adenosine receptor represents a potential therapeutic strategy to limit choroidal neovascularization.

The concurrent antagonism or modulation of other adenosine receptors may provide additional benefit and enhance the efficacy of approaches aimed at suppressing choroidal neovascularization.

Aging reduces the tissue regenerative capacity, promotes chronic inflammation, and contributes to neurodegenerative diseases, including age-related macular degeneration (AMD). AMD is a leading cause of vision loss in older adults and manifests as dry (atrophic) or wet (neovascular) disease. Although dry AMD is more prevalent, neovascular AMD (nAMD) causes the most severe vision impairment and remains a major public health burden. Oxidative stress-mediated inflammation and dysfunction of retinal pigment epithelium (RPE) cells and choriocapillaris drive early AMD. Neovascular AMD is marked by pathologic choroidal neovascularization (CNV), driven largely by dysregulated VEGF signaling. Anti-VEGF therapies are the current standard of care for nAMD but require frequent intravitreal injections, carry procedure-related risks, and are ineffective in a substantial subset of patients, underscoring the need for new therapeutic approaches. Caffeine, a widely consumed and well-tolerated adenosine receptor antagonist, has emerging relevance in vascular regulation and inflammatory signaling. Extracellular ATP and its metabolites, including adenosine, accumulate under stress and act through purinergic receptors to influence angioinflammatory processes. We recently showed that systemic caffeine administration suppressed CNV in vivo, an effect partly reproduced by the adenosine receptor A2A antagonist Istradefylline. Here, we investigated the cell-autonomous effects of caffeine on mouse choroidal endothelial cells, focusing on its role as an adenosine receptor antagonist and its potential to inhibit pathological neovascularization.