Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands.
Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands.
复制标题
作者：
炎症、氧化应激和新生血管形成的相互作用正在成为从组织愈合/重塑到癌症进展的众多过程的重要机制。尽管缺氧驱动的血管生成的机制已被充分了解，但炎症诱导的氧化与新生血管生长之间的联系仍然不清楚。在这里，我们发现脂质氧化的最终产物，ω-(2-羧乙基)吡咯(CEP)和其他相关吡咯，在炎症和伤口愈合过程中产生，并在衰老组织和高度血管化的肿瘤中大量积累。羧烷基吡咯的分子模式可被 Toll 样受体 2 (TLR2) 识别，但不能被 TLR4 和内皮细胞 (EC) 上的清道夫受体识别，从而导致不依赖于 VEGF 的血管生成反应。 CEP 通过 TLR2 信号传导以 MyD88 依赖性方式促进后肢缺血和伤口愈合模型中的血管生成。内源性羧烷基吡咯的中和会损害伤口愈合和组织血管重建，并减少肿瘤血管生成。 TLR2 和 MyD88 都是 CEP 诱导的 Rac1 刺激和内皮迁移所必需的。总之，这些发现确立了 TLR2 作为氧化相关分子模式传感器的新功能，提供了连接炎症、氧化应激、先天免疫和血管生成的关键环节。
Reciprocity of inflammation, oxidative stress and neovascularization is emerging as an important mechanism underlying numerous processes from tissue healing/remodeling to cancer progression. Whereas the mechanism of hypoxia-driven angiogenesis is well understood, the link between inflammation-induced oxidation and de novo blood vessel growth remains obscure. Here we show that the end products of lipid oxidation, ω-(2-carboxyethyl)pyrrole (CEP) and other related pyrroles, are generated during inflammation and wound healing and accumulate at high levels in aging tissues and in highly vascularized tumors. The molecular patterns of carboxyalkylpyrroles are recognized by Toll-like receptor 2 (TLR2), but not TLR4 nor scavenger receptors on endothelial cells (ECs), leading to a VEGF-independent angiogenic response. CEP promoted angiogenesis in hind limb ischemia and wound healing models through TLR2 signaling in a MyD88-dependent manner. Neutralization of endogenous carboxyalkylpyrroles impaired wound healing and tissue re-vascularization and diminished tumor angiogenesis. Both TLR2 and MyD88 are required for CEP-induced stimulation of Rac1 and endothelial migration. Together, these findings establish a new function of TLR2 as a sensor of oxidation-associated molecular patterns, providing a key link connecting inflammation, oxidative stress, innate immunity and angiogenesis.
登录
查看更多内容
影响因子：
30.5
作者：
Arbibe, L;Mira, JP;Knaus, UG
通讯作者：
Knaus, UG
影响因子：
15.9
作者：
Mullick, AE;Tobias, PS;Curtiss, LK
通讯作者：
Curtiss, LK
影响因子：
82.9
作者：
Chen, JH;Somanath, PR;Byzova, TV
通讯作者：
Byzova, TV
影响因子：
56.9
作者：
Aliprantis, AO;Yang, RB;Zychlinsky, A
通讯作者：
Zychlinsky, A
DOI：
10.1073/pnas.222551899
发表时间：
2002-11-12
影响因子：
11.1
作者：
Crabb, JW;Miyagi, M;Hollyfield, JG
通讯作者：
Hollyfield, JG