Attenuation of Choroidal Neovascularization by Histone Deacetylase Inhibitor

Abstract

Choroidal neovascularization (CNV) is a blinding complication of age-related macular degeneration that manifests as the growth of immature choroidal blood vessels through Bruch’s membrane, where they can leak fluid or hemorrhage under the retina. Here, we demonstrate that the histone deacetylase inhibitor (HDACi) trichostatin A (TSA) can down-regulate the pro-angiogenic hypoxia-inducible factor-1α and vascular endothelial growth factor (VEGF), and up-regulate the anti-angiogenic and neuro-protective pigment epithelium derived factor in human retinal pigment epithelial (RPE) cells. Most strikingly, TSA markedly down-regulates the expression of VEGF receptor-2 in human vascular endothelial cells and, thus, can knock down pro-angiogenic cell signaling. Additionally, TSA suppresses CNV-associated wound healing response and RPE epithelial-mesenchymal transdifferentiation. In the laser-induced model of CNV using C57Bl/6 mice, systemic administration of TSA significantly reduces fluorescein leakage and the size of CNV lesions at post—laser days 7 and 14 as well as the immunohistochemical expression of VEGF, VEGFR2, and smooth muscle actin in CNV lesions at post-laser day 7. This report suggests that TSA, and possibly HDACi’s in general, should be further evaluated for their therapeutic potential for the treatment of CNV.

Hypoxia‐induced vascular endothelial growth factor secretion by retinal pigment epithelial cells is inhibited by melatonin via decreased accumulation of hypoxia‐inducible factors‐1α protein

“…Loss of RPE cells causes atrophy of choriocapillaris ,. Hypoxia stimulated the expression and secretion of VEGF by RPE cells via the accumulation of HIF‐1α protein in the cells …”

“…Retinal pigment epithelial cells express and secrete VEGF, which is the main source of VEGF in the retina . Loss of RPE cells causes atrophy of choriocapillaris ,.…”

“…[3][4][5] Retinal pigment epithelial cells express and secrete VEGF, which is the main source of VEGF in the retina. [39][40][41][42][43][44][45] Loss of RPE cells causes atrophy of choriocapillaris. 46 Melatonin, a neurohormone, is mainly produced in the pineal gland.…”

Pathogenic role and therapeutic potential of pleiotrophin in mouse models of ocular vascular disease

“…CNV lesions were analyzed by fluorescein angiography on Day 7. Briefly, fluorescein sodium (2.5%, 0.1 mL, Akorn) was intraperitoneally injected into mice [24, 31]. Fluorescein angiography was performed 6 min post injection using Heidelberg Engineering Multiline HRA SN 2884 Imaging System.…”

“…Eyecups of the retinal pigment epithelium (RPE)-choroid-sclera were isolated and fixed in 4% paraformaldehyde. Eyecups were incubated in PBS containing 0.5% Triton X-100 at 4°C for 24 h and stained with Alexa Fluor 488-isolectin B4 (10 μg/ml, 0.5 ml/retina) overnight at room temperature [24, 31]. After washing, eyecups were flat mounted and analyzed by confocal microscopy.…”