Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands

West, et al. 2010. Nature 467: 972-976

Speaker: Tzu-Hao Yeh (葉子豪)                           Time: 13:10~14:00, Mar. 23, 2011

Commentator: Dr. Li-Wha Wu (吳梨華 老師)    Place: Room 601

Abstract:

Angiogenesis is frequently associated with inflammation, where inflammatory cells produce oxidative products resulting in oxidative stress. While the cells can induce neovascularization through production of proangiogenic factors such as vascular endothelial growth factor (VEGF), the authors propose that oxidative products may also contribute to angiogenesis. Their first clue is that w-(2-carboxyethyl) pyrrole (CEP) and other oxidative lipid-protein adducts as end products of oxidative stress accumulate in the retina of macular degeneration, where abnormal vessel growth occurs [1]. In this study, they test several models of neovascularization and inflammation, including wound healing, melanoma tumors, and ischaemia. CEP accumulation coincides with angiogenesis in these models. Notably, treatment with CEP or other similarly modified compounds induceneovascularization both in vitro and in vivo, and the angiogenic effect is not inhibited by blockage of the VEGF pathway. Further searching for endothelial cell-expressing receptors that recognize CEP and mediate CEP-induced angiogenesis, the authors identify that Toll-like receptor (TLR)2 is critical and TLR1 is also involved, while TLR4, TLR6 and scavenger receptors are dispensable. TLR2 can recognize many molecular patterns and contribute to innate immunity and inflammation [2]. Downstream of TLR2, MyD88 mediates CEP-induced Rac1 activation and endothelial migration. In adoptive transfer studies, TLR2 expression in non-hematopoietic cells is important for neovascularization in wound healing and melanoma growth. By using antibodies neutralizing CEP and VEGF, the authors demonstrate that the two factors exert an additive effect on angiogenesis and tumor growth of melanoma. This study reveals a novel link among innate immunity, oxidation and angiogenesis, providing a new therapeutic target to treat diseases involving inflammation and angiogenesis.

References:

1.          Ebrahem, et al. (2006) Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: Implications for age-related macular degeneration. Proc. Natl. Acad. Sci. USA 103, 13480-13484.

2.          Zahringer, et al. (2008) TLR2－promiscuous or specific? A critical re-evaluation of a receptor expressing apparent broad specificity. Immunobiology 213, 205-224.