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 / Cho, W. G.; Albuquerque, R. J.; Kleinman, M. E.; Tarallo, V.; Greco, Adelaide; Nozaki, M.; Green, M. G.; Baffi, J. Z.; Ambati, B. K.; De Falco, M.; Alexander, J. S.; Brunetti, Arturo; De F. a. l. c. o., S; Ambati, J.. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 1091-6490. - STAMPA. - 106:17(2009), pp. 7137-7142. [10.1073/pnas.0812317106]

Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth.

GRECO, ADELAIDE;BRUNETTI, ARTURO;
2009

Abstract

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.
2009
Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth / Cho, W. G.; Albuquerque, R. J.; Kleinman, M. E.; Tarallo, V.; Greco, Adelaide; Nozaki, M.; Green, M. G.; Baffi, J. Z.; Ambati, B. K.; De Falco, M.; Alexander, J. S.; Brunetti, Arturo; De F. a. l. c. o., S; Ambati, J.. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 1091-6490. - STAMPA. - 106:17(2009), pp. 7137-7142. [10.1073/pnas.0812317106]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/360462
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