Vascular Microenvironment Laboratory, Department of Biomedical Sciences and Pharmacology, College of Medicine, Seoul National University, Seoul, Republic of Korea.
Vascular Microenvironment Laboratory, Department of Biomedical Sciences and Pharmacology, College of Medicine, Seoul National University, Seoul, Republic of Korea; Ischemic/Hypoxic Disease Institute and Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Republic of Korea.
Biochem Biophys Res Commun. 2019 Oct 15;518(2):286-293. doi: 10.1016/j.bbrc.2019.08.048. Epub 2019 Aug 16.
The regulation of endothelial cell (EC) permeability is critical for the physiological homeostasis of blood vessels and tissues. The elevation of pro-inflammatory cytokines is highly associated with lesions, such as the increased vascular permeability of diabetic retinas. We have previously reported that interleukin-6 (IL-6) increases EC permeability through the downregulation of tight junction protein expression. Angiopoietin 1 (Ang1) has an anti-permeability function, but the effect of Ang1 on vascular permeability induced by inflammatory cytokines is unclear. In the present study, we investigated the effect of Ang1 on IL-6-induced EC permeability and its underlying molecular mechanisms. We demonstrated that Ang1 inhibited the IL-6-induced increase in EC permeability by inhibiting the reductions in the levels of tight junction protein ZO-1 and occludin, which was related to the decrease in vascular endothelial growth factor (VEGF) secretion through the inhibition of STAT3 activation by Ang1. Mechanistically, Ang1 induced the dissociation of the tyrosine phosphatase SHP-1 from the Tie2 receptor and increased the binding of SHP-1 to JAK1, JAK2, and STAT3, which are IL-6 downstream signaling proteins. We conclude that SHP-1 plays an important role in the Ang1-induced inhibition of JAK/STAT3 signaling. These results provide evidence for a potential beneficial role of Ang1 in suppressing the vascular permeability induced by the pro-inflammatory cytokine IL-6 in diabetic retinopathy.
内皮细胞（EC）通透性的调节对于血管和组织的生理稳态至关重要。促炎细胞因子的升高与病变高度相关，例如糖尿病视网膜血管通透性增加。我们之前曾报道过，白细胞介素 6（IL-6）通过下调紧密连接蛋白的表达来增加 EC 的通透性。血管生成素 1（Ang1）具有抗通透性作用，但 Ang1 对炎性细胞因子诱导的血管通透性的影响尚不清楚。在本研究中，我们研究了 Ang1 对 IL-6 诱导的 EC 通透性的影响及其潜在的分子机制。我们证明，Ang1 通过抑制血管内皮生长因子（VEGF）的分泌来抑制 IL-6 诱导的 EC 通透性增加，这与 Ang1 通过抑制 STAT3 激活来降低紧密连接蛋白 ZO-1 和闭合蛋白的水平有关。在机制上，Ang1 诱导酪氨酸磷酸酶 SHP-1 从 Tie2 受体解离，并增加 SHP-1 与 JAK1、JAK2 和 STAT3 的结合，后者是 IL-6 下游信号蛋白。我们得出结论，SHP-1 在 Ang1 诱导的 JAK/STAT3 信号抑制中起重要作用。这些结果为 Ang1 在抑制糖尿病视网膜病变中促炎细胞因子 IL-6 诱导的血管通透性中的潜在有益作用提供了证据。
