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Pierre Hardy, Houda Tahiri, Chun Yang; Choroidal Antiangiogenic Effects of Lymphocyte-Derived Microparticles are Mediated Through PEDF and Neurotrophin Receptor p75NTR Signalling Pathways. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4360.
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The importance of identifying VEGF-independent pathways in pathological angiogenesis is increasingly recognized as a result of emerging drug resistance to anti-VEGF therapies. Human T-Lymphocyte-Derived Microparticles (LMPs) significantly inhibit angiogenesis in several ocular neovascularization (NV) models including inflammatory corneal NV and oxygen-induced retinopathy. Both pigment epithelium-derived factor (PEDF) and the neurotrophins (NT) low-affinity p75NTR receptor have shown antiangiogenic effects, more specifically, the balance between VEGF and PEDF play an important role in choroidal angiogenesis. Our study is designed to determine how LMPs modulate the pro and antiangiogenic microenvironments in choroidal angiogenesis.
Antiangiogenic effects of LMPs were determined by using rat model of choroidal explants. LMPs were produced by treatment of human T lymphocytes with actinomycin D and their effects were studied on several ocular cell lines. Cell viability (MTT assay), proliferation ([3H]-thymidine DNA incorporation), migration assays and apoptosis (DNA fragmentation assays) were tested in cell lines. Choroidal expression of VEGF, PEDF, nerve growth factor (NGF), neurotrophin-3 and -4 (NT-3,-4) and p75NTR were demonstrated by Western blots and RT-PCR. Secretion of neurotrophin into the culture medium was analyzed by enzyme immunoassay (ELISA).
Choroidal NV was suppressed by more than 50% after 72h of LMPs treatments. LMPs targeting acted not only on multiple cell types important for choroidal angiogenesis, such as vascular endothelial cells (inhibit human retinal endothelial cell proliferation by 55%, macrophages (RAW 264.7), and RPE cells (ARPE19), but also on the expression of important angiogenic genes, such as VEGF, VEGF receptors, PEDF and PEDF receptors. At a molecular level, LMPs regulated neurotrophins and their receptors expression both in vitro and in vivo. Activation of neurotrophins and their receptors impaired angiogenesis. Inhibition of p75NTR abolished the antiangiogenic effect of LMPs. p75NTR activation by LMPs induces EC apoptosis and cell cycle arrest and contributes to antiangiogenic effect of LMPs.
LMPs are important candidate for antiangiogenic therapy. PEDF and neurotrophin induction by LMPs may be of therapeutic value in treating ocular neovascular diseases. Our data demonstrate that choroidal tissues have the capacity to synthesize neurotrophins, and that various stimulations can up-regulate gene and protein expression of neurotrophins.
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