Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth(403 views) Cho WG, Albuquerque RJ, Kleinman ME, Tarallo V, Greco A, Nozaki M, Green MG, Baffi JZ, Ambati BK, De Falco M, Alexander JS, Brunetti A, De Falco S, Ambati J
P Natl Acad Sci Usa (ISSN: 0027-8424, 1091-6490, 0027-8424print), 2009 Apr 28; 106(17): 7137-7142.
Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, United States
Department of Physiology, University of Kentucky, Lexington, KY 40536, United States
Institute of Genetics and Biophysics Adriano Buzzati-Traverso, Consiglio Nazionale delle Ricerche, Naples 80131, Italy
Department of Biomorphological and Functional Sciences, University Federico II, Centro di Ingegneria Genetica, Naples 80131, Italy
Department of Anesthesiological, Surgical and Emergency Sciences, V Unit of Surgery and Advanced Surgical Procedures, Second University of Naples, Naples 80100, Italy
Department of Molecular and Cellular Physiology, Louisiana State University, Health Sciences Center, Shreveport, LA 71130-3932, United States
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Ranjith-Kumar, C. T., Biochemical and functional analyses of the human Toll-like receptor 3 ectodomain (2007) J Biol Chem, 282, pp. 7668-7678
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Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth
Neovascularization in response to tissue injury consists of the dual invasion of blood (hemangiogenesis) and lymphatic (lymphangiogenesis) vessels. We reported recently that 21-nt or longer small interfering RNAs (siRNAs) can suppress hemangiogenesis in mouse models of choroidal neovascularization and dermal wound healing independently of RNA interference by directly activating Toll-like receptor 3 (TLR3), a double-stranded RNA immune receptor, on the cell surface of blood endothelial cells. Here, we show that a 21-nt nontargeted siRNA suppresses both hemangiogenesis and lymphangiogenesis in mouse models of neovascularization induced by corneal sutures or hindlimb ischemia as efficiently as a 21-nt siRNA targeting vascular endothelial growth factor-A. In contrast, a 7-nt nontargeted siRNA, which is too short to activate TLR3, does not block hemangiogenesis or lymphangiogenesis in these models. Exposure to 21-nt siRNA, which we demonstrate is not internalized unless cell-permeating moieties are used, triggers phosphorylation of cell surface TLR3 on lymphatic endothelial cells and induces apoptosis. These findings introduce TLR3 activation as a method of jointly suppressing blood and lymphatic neovascularization and simultaneously raise new concerns about the undesirable effects of siRNAs on both circulatory systems.
Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth
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