Integrative Biosciences Center, Wayne State University, Detroit, MI, 48202, USA.
Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, MI, 48202, USA.
Commun Biol. 2023 May 13;6(1):516. doi: 10.1038/s42003-023-04905-z.
Vascular adhesion molecules play an important role in various immunological disorders, particularly in cancers. However, little is known regarding the role of these adhesion molecules in proliferative retinopathies. We observed that IL-33 regulates VCAM-1 expression in human retinal endothelial cells and that genetic deletion of IL-33 reduces hypoxia-induced VCAM-1 expression and retinal neovascularization in C57BL/6 mice. We found that VCAM-1 via JunB regulates IL-8 promoter activity and expression in human retinal endothelial cells. In addition, our study outlines the regulatory role of VCAM-1-JunB-IL-8 signaling on retinal endothelial cell sprouting and angiogenesis. Our RNA sequencing results show an induced expression of CXCL1 (a murine functional homolog of IL-8) in the hypoxic retina, and intravitreal injection of VCAM-1 siRNA not only decreases hypoxia-induced VCAM-1-JunB-CXCL1 signaling but also reduces OIR-induced sprouting and retinal neovascularization. These findings suggest that VCAM-1-JunB-IL-8 signaling plays a crucial role in retinal neovascularization, and its antagonism might provide an advanced treatment option for proliferative retinopathies.
血管黏附分子在各种免疫性疾病中发挥重要作用，特别是在癌症中。然而，关于这些黏附分子在增殖性视网膜病变中的作用知之甚少。我们观察到，IL-33 可调节人视网膜血管内皮细胞中 VCAM-1 的表达，而 IL-33 的基因缺失可减少 C57BL/6 小鼠缺氧诱导的 VCAM-1 表达和视网膜新生血管形成。我们发现 VCAM-1 通过 JunB 调节人视网膜血管内皮细胞中 IL-8 启动子的活性和表达。此外，我们的研究概述了 VCAM-1-JunB-IL-8 信号通路对视网膜内皮细胞出芽和血管生成的调节作用。我们的 RNA 测序结果显示，缺氧视网膜中 CXCL1（IL-8 的一种鼠类功能同源物）的表达被诱导，而玻璃体内注射 VCAM-1 siRNA 不仅降低了缺氧诱导的 VCAM-1-JunB-CXCL1 信号通路，还减少了 OIR 诱导的出芽和视网膜新生血管形成。这些发现表明，VCAM-1-JunB-IL-8 信号通路在视网膜新生血管形成中发挥关键作用，其拮抗作用可能为增殖性视网膜病变提供一种先进的治疗选择。
