State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 S Xianlie Rd, Guangzhou 510060, China.
Arterioscler Thromb Vasc Biol. 2011 May;31(5):1024-32. doi: 10.1161/ATVBAHA.111.224048. Epub 2011 Mar 3.
Inflammation is closely linked to angiogenesis, and Toll-like receptors (TLRs) are the key mediators of inflammatory responses. However, the impact of TLRs on angiogenesis is incompletely understood. In this study, we determined the involvement of TLRs in angiogenesis.
In a mouse model of alkali-induced corneal neovascularization (CNV), we found that CNV was attenuated in TLR4-/- but not TLR2-/- mice. Further study revealed that the absence of TLR4 led to decreased production of proangiogenic factors in association with reduced accumulation of macrophages at the site of wounds, which was associated with reduced expression of high-mobility group box-1 (HMGB1) protein, an endogenous ligand for TLR4. Topical application of HMGB1 to the injured cornea promoted CNV with increased macrophage accumulation in wild-type mice but not in TLR4-/- mice. HMGB1 treatment in vitro also promoted the production of proangiogenic factors by mouse macrophages in a TLR4-dependent manner. Furthermore, antagonists of HMGB1 and TLR4 reduced CNV and macrophage recruitment in the injured cornea of wild-type mice.
Our results suggest that the release of HMGB1 in the wounds initiates TLR4-dependent responses that contribute to neovascularization. Thus, targeting HMGB1-TLR4 signaling cascade may constitute a novel therapeutic approach to angiogenesis-related diseases.
炎症与血管生成密切相关，而 Toll 样受体（TLRs）是炎症反应的关键介质。然而，TLRs 对血管生成的影响尚不完全清楚。本研究旨在探讨 TLRs 在血管生成中的作用。
在碱性诱导的角膜新生血管化（CNV）小鼠模型中，我们发现 TLR4-/- 小鼠的 CNV 减轻，而 TLR2-/- 小鼠则无此作用。进一步研究表明，TLR4 的缺失导致促血管生成因子的产生减少，与伤口部位巨噬细胞积累减少有关，这与高迁移率族蛋白 1（HMGB1）蛋白表达减少有关，HMGB1 是 TLR4 的内源性配体。将 HMGB1 局部应用于受损角膜可促进 CNV，并增加野生型小鼠中巨噬细胞的积累，但在 TLR4-/- 小鼠中则无此作用。HMGB1 在体外处理也可促进小鼠巨噬细胞产生促血管生成因子，且依赖于 TLR4。此外，HMGB1 和 TLR4 的拮抗剂可减少野生型小鼠受损角膜中的 CNV 和巨噬细胞募集。
我们的结果表明，伤口中 HMGB1 的释放引发 TLR4 依赖性反应，从而促进血管生成。因此，靶向 HMGB1-TLR4 信号通路可能成为与血管生成相关疾病的一种新的治疗方法。
