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Pierre Hardy, Houda Tahiri, Chun Yang, Francois Duhamel, Carmen Gagnon; Lymphocytes-derived Microparticles Modulate Angiostatic Factors In Retinal Pigment Epithelium Cells. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2947.
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The retinal pigment epithelium cells (RPE) play a central role in retinal vascularisation. RPE cells produce a variety of growth factors helping to maintain the structural integrity of choriocapillaris endothelium. We have previously reported that Human T-lymphocyte-derived microparticles (LMPs) significantly inhibit pathological angiogenesis interfering through VEGF/VEGFR2 signalling pathway in vitro and vivo experiments. In addition, we recently observed the strong antiangiogenic effects of LMPs on choroidal neovascularization and overexpression of the neurotrophins low-affinity p75NTR receptor in cultured choroidal explants. This study is designed to determine how RPE cells mediate the anti-angiogenic effects of LMPs in the choroidal neovascularisation.
LMPs were produced by treatment of human T-lymphocytes with actinomycin D. The rat model of choroidal explants was used to determine the antiangiogenic effects of LMPs. RPE-removed choroidal tissues were prepared using dispase enzyme solution. Expression of angiostatic factors from choroidal and RPE-removed choroidal tissues were assessed by RT- PCR. Caspase-3 was used to determine cell apoptosis in choroidal explants. Primary cultured RPE cells were used in in vitro experiments.
LMPs time-dependently inhibited choroidal neovascularisation (NV). Removing RPE cells from the choroidal explants resulted in a strong abolishment of the antiangiogenic effects of LMPs. Accordingly, LMPs significantly increased the expression of angiostatic factors in choroidal explants such as pigment epithelial-derived factor (PEDF), neurotrophin growth factor (NGF) but not in RPE-removed choroids. Interestingly, the culture medium from RPE cells was able to rescue the anti-angiogenic effect of LMPs on choroidal NV. Using specific antibodies against PEDF, p75NTR or shRNA against p75NTR significantly blocked the anti-angiogenic effect of LMPs. Consequently, the LMPs-induced NGF caused a significantly apoptosis of choroidal endothelial cells.
The strong antiangiogenic effects of LMPs on choroidal NV are largely dependent on targeting both RPE and choroidal endothelial cells_which play important roles in the choroidal angiogenesis. More specifically, PEDF and NGF, the anti-angiogenic factors produced from RPE cells, are important mediators of LMPs on choroidal NV. Our data suggested that LMPs may be of therapeutic value in treating ocular neovascular diseases.
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