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Rebecca Stevens, Peter Campochiaro, Ji-kui Shen, Brian Oveson, Sean Hackett, Nathan Mata; Fenretinide Inhibits Ocular Neovascularization (NV) by Upregulation of Bone Morphogenic Protein-2 (BMP-2) and Reduction of Inflammatory Macrophages and VEGF. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1956.
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© ARVO (1962-2015); The Authors (2016-present)
N-(4-hydroxyphenyl) retinamide (4HPR; fenretinide), a synthetic retinoic acid derivative, is a promising chemopreventive agent for tumors. A recent clinical trial showed that 4HPR reduced the incidence of choroidal NV in patients with age-related macular degeneration and geographic atrophy. We sought to investigate the effects of 4HPR in mouse models of ocular neovascularization (NV).
The effects of intraocular and systemic 4HPR were tested in mice with laser-induced choroidal NV, oxygen-induced ischemic retinopathy, and rho/VEGF transgenic mice. Levels of various mRNAs were measured by real-time RT-PCR. The effects of 4HPR or all-trans retinoic acid (atRA) on AP1 activity was tested with a dual luciferase expression assay using a pGL3-AP1 artificial promoter construct in the RPE16 cell line.
Oral administration of 4HPR suppressed choroidal NV and intraocular injection of 10-7or 10-8M 4HPR significantly suppressed NV in each of the 3 mouse models. Injection of 4HPR also reduced the influx of macrophages into ischemic retina. Unlike atRA, 4HPR did not stimulate expression of RARs or RXRs in the retina after intraocular injection, nor did it reduce expression of AP1-responsive genes. In cultured RPE cells, atRA, but not 4HPR, suppressed AP1 activity. After intraocular injection of 10-7or 10-8M 4HPR in mice with ischemic retinopathy, there was a significant reduction in mRNA for VEGF and CCL2, and an increase in mRNA for BMP2. Intraocular injection of recombinant BMP2 significantly suppressed ischemia-induced NV.
Systemic or intraocular 4HPR suppresses ocular NV, not through activation of RARs or RXRs and suppression of AP1, but rather by increasing expression of BMP2 and reducing inflammatory macrophages with concomitant reduction in VEGF.
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