Role of receptor-mediated endocytosis in the antiangiogenic effects of human T lymphoblastic cell-derived microparticles

Microparticles possess therapeutic potential regarding angiogenesis. We have demonstrated the contribution of apoptotic human CEM T lymphocyte-derived microparticles (LMPs) as inhibitors of angiogenic responses in animal models of inflammation and tumor growth. In the present study, we characterized...

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Published in:American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2012-04, Vol.302 (8), p.R941-R949
Main Authors: Yang, Chun, Xiong, Wei, Qiu, Qian, Shao, Zhuo, Shao, Zuo, Hamel, David, Tahiri, Houda, Leclair, Grégoire, Lachapelle, Pierre, Chemtob, Sylvain, Hardy, Pierre
Format: Article
Language:English
Subjects:
Angiogenesis
Animals
Cell growth
Cell Line
Cell Movement - physiology
Cell Proliferation
Cell-Derived Microparticles - physiology
Endocytosis
Endocytosis - physiology
Endothelial Cells - physiology
Endothelium, Vascular - pathology
Endothelium, Vascular - physiopathology
Humans
Lymphocyte receptors
Rats
Retinal Neovascularization - pathology
Retinal Neovascularization - physiopathology
Retinal Vessels - pathology
Retinal Vessels - physiopathology
T cell receptors
T-Lymphocytes - pathology
T-Lymphocytes - physiology
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Summary:Microparticles possess therapeutic potential regarding angiogenesis. We have demonstrated the contribution of apoptotic human CEM T lymphocyte-derived microparticles (LMPs) as inhibitors of angiogenic responses in animal models of inflammation and tumor growth. In the present study, we characterized the antivascular endothelial growth factor (VEGF) effects of LMPs on pathological angiogenesis in an animal model of oxygen-induced retinopathy and explored the role of receptor-mediated endocytosis in the effects of LMPs on human retinal endothelial cells (HRECs). LMPs dramatically inhibited cell growth of HRECs, suppressed VEGF-induced cell migration in vitro experiments, and attenuated VEGF-induced retinal vascular leakage in vivo. Intravitreal injections of fluorescently labeled LMPs revealed accumulation of LMPs in retinal tissue, with more than 60% reductions of the vascular density in retinas of rats with oxygen-induced neovascularization. LMP uptake experiments demonstrated that the interaction between LMPs and HRECs is dependent on temperature. In addition, endocytosis is partially dependent on extracellular calcium. RNAi-mediated knockdown of low-density lipoprotein receptor (LDLR) reduced the uptake of LMPs and attenuated the inhibitory effects of LMPs on VEGF-A protein expression and HRECs cell growth. Intravitreal injection of lentivirus-mediated RNA interference reduced LDLR protein expression in retina by 53% and significantly blocked the antiangiogenic effects of LMPs on pathological vascularization. In summary, the potent antiangiogenic LMPs lead to a significant reduction of pathological retinal angiogenesis through modulation of VEGF signaling, whereas LDLR-mediated endocytosis plays a partial, but pivotal, role in the uptake of LMPs in HRECs.
ISSN:0363-6119
1522-1490
DOI:10.1152/ajpregu.00527.2011