CAMKII as a therapeutic target for growth factor–induced retinal and choroidal neovascularization
Sadaf Ashraf, Samuel Bell, Caitriona O’Leary, Paul Canning, Ileana Micu, Jose A. Fernandez, Michael O’Hare, Peter Barabas, Hannah McCauley, Derek P. Brazil, Alan W. Stitt, J. Graham McGeown, Tim M. Curtis
Sadaf Ashraf, Samuel Bell, Caitriona O’Leary, Paul Canning, Ileana Micu, Jose A. Fernandez, Michael O’Hare, Peter Barabas, Hannah McCauley, Derek P. Brazil, Alan W. Stitt, J. Graham McGeown, Tim M. Curtis
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Research Article Angiogenesis Ophthalmology

CAMKII as a therapeutic target for growth factor–induced retinal and choroidal neovascularization

Abstract

While anti-VEGF drugs are commonly used to inhibit pathological retinal and choroidal neovascularization, not all patients respond in an optimal manner. Mechanisms underpinning resistance to anti‑VEGF therapy include the upregulation of other proangiogenic factors. Therefore, therapeutic strategies that simultaneously target multiple growth factor signaling pathways would have significant value. Here, we show that Ca2+/calmodulin-dependent kinase II (CAMKII) mediates the angiogenic actions of a range of growth factors in human retinal endothelial cells and that this kinase acts as a key nodal point for the activation of several signal transduction cascades that are known to play a critical role in growth factor–induced angiogenesis. We also demonstrate that endothelial CAMKIIγ and -δ isoforms differentially regulate the angiogenic effects of different growth factors and that genetic deletion of these isoforms suppresses pathological retinal and choroidal neovascularization in vivo. Our studies suggest that CAMKII could provide a novel and efficacious target to inhibit multiple angiogenic signaling pathways for the treatment of vasoproliferative diseases of the eye. CAMKIIγ represents a particularly promising target, as deletion of this isoform inhibited pathological neovascularization, while enhancing reparative angiogenesis in the ischemic retina.

Authors

Sadaf Ashraf, Samuel Bell, Caitriona O’Leary, Paul Canning, Ileana Micu, Jose A. Fernandez, Michael O’Hare, Peter Barabas, Hannah McCauley, Derek P. Brazil, Alan W. Stitt, J. Graham McGeown, Tim M. Curtis

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Figure 7

Oxygen-induced retinopathy (OIR) in CAMKIIγ- and -δ–KO mice.

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Oxygen-induced retinopathy (OIR) in CAMKIIγ- and -δ–KO mice. Pups were e...
Pups were exposed to hyperoxia (75% O2) from P7–P12, followed by 5 days in room air to induce vascular insufficiency and preretinal neovascularization. Some mice were euthanized at P12 to assess the degree of retinal vascular regression. (A and B) Left and middle, isolectin B4–stained flat‑mounted retinas from CAMKIIγ and -δ WT and homozygous KO OIR mice at P12 and P17. Red (solid) and yellow (dashed) lines demarcate total retinal areas and avascular areas, respectively. Scale bars: 1.0 mm. Right, magnified regions of the P17 retinal flatmounts. Scale bars: 200 μm. (C and D) Box-and-whisker plots (min, max, 25th–75th percentile, median) of avascular, neovascular, and normal vascular areas expressed as a percentage of the total retinal area for the various cohorts of mice at P12 and P17. Neovascularization was absent at P12 and, therefore, has not been plotted. *P < 0.05, **P < 0.01, ***P < 0.001 based on ANOVA (avascular and normal vascular) and 2-tailed Student t test (neovascular). Data is derived from a minimum of 10 mice per group.