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Zaheer Ali, Anthony Mukwaya, Anton Lennikov, Beatrice Peebo, Neil S Lagali, Yihai Cao, Julianna Kele Olovsson, Lasse Jensen; Fundamentally different mechanisms regulate angiogenesis in the retina and choroid. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4067. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The molecular and cellular mechanisms underlying the angiogenic switch in wet AMD are poorly understood. Commonly used rodent models, including the laser-induced choroidal neovascularization (CNV) model, incompletely recapitulate the clinical disease history of patients developing wet AMD, especially considering that most patients present with occult rather than classical CNV, and thus have a relatively intact RPE/Bruch’s membrane and exclusively sub-retinal vessel growth and edema, unlike the situation in the laser-induced CNV model in rodents. Our hypothesis is that zebrafish may constitute an attractive alternative model system for occult CNV. The purpose of our research is to demonstrate hypoxia-induced, occult CNV in adult zebrafish and to delineate previously unknown mechanisms underlying this process.
Zebrafish have recently emerged as powerful systems for mechanistic studies of disease development, including photoreceptor degeneration and pathological changes in the retinal vasculature. Here we take advantage of a recently developed hypoxia-induced angiogenesis model in adult zebrafish, coupled with transcriptomic profiling, histological evaluations and pharmacologic inhibition studies, to study the mechanisms underlying occult CNV.
As the zebrafish choroid vasculature is poorly characterized, here we first present a comprehensive, comparative anatomical, physiological, cellular and molecular characterization of choroidal vessels in adult zebrafish. We found that the choriocapillaries are highly similar to those found in humans and other mammals both anatomically, histologically and physiologically. We further demonstrate that treatment with hypoxic water (10% of the oxygen found in air-saturated water) during 10 days is sufficient to induce robust CNV without impairing the RPE/Bruch’s membrane barrier. Interestingly, hypoxia-induced CNV occurred by an intussusception-like process. We found that hypoxia-induced CNV require VEGF-A-VEGFR2 signaling which lead to intussusception through reorganizing the microtubule, but not the actin cytoskeleton in the endothelial cells.
The findings presented here demonstrate that zebrafish constitute an important alternative to mouse models for (occult) CNV and therefore wet AMD research, that hypoxia as an isolated factor drives CNV and that occult CNV may primarily occur by a process resembling intussusception.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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