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

Won Gil Cho, Romulo J C Albuquerque, Mark E. Kleinman, Valeria Tarallo, Adelaide Greco, Miho Nozaki, Martha G. Green, Judit Z. Baffi, Balamurali K. Ambati, Massimo De Falco, Jonathan S. Alexander, Arturo Brunetti, Sandro De Falco, Jayakrishna Ambati

Research output: Contribution to journalArticlepeer-review


Neovascularization in response to tissue injury consists of the dual invasion of blood (hemangiogenesis) and lymphatic (lymphangio-genesis) 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 lym-phangiogenesis in mouse models of neovascularization induced by corneal sutures or hindlimb ischemia as efficiently as a 21-nt si RNA 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.

Original languageEnglish
Pages (from-to)7137-7142
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
Publication statusPublished - Apr 28 2009


  • Angiogenesis
  • Innate immunity
  • Ischemia
  • Lymphangiogenesis
  • Wound healing

ASJC Scopus subject areas

  • General


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