Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC H1T 2M4, Canada.
Department of Neurology-Neurosurgery, McGill University, Montreal, QC H3A 2B4 Canada.
Proc Natl Acad Sci U S A. 2019 Mar 5;116(10):4538-4547. doi: 10.1073/pnas.1814711116. Epub 2019 Feb 20.
Diabetic macular edema is a major complication of diabetes resulting in loss of central vision. Although heightened vessel leakiness has been linked to glial and neuronal-derived factors, relatively little is known on the mechanisms by which mature endothelial cells exit from a quiescent state and compromise barrier function. Here we report that endothelial NOTCH1 signaling in mature diabetic retinas contributes to increased vascular permeability. By providing both human and mouse data, we show that NOTCH1 ligands JAGGED1 and DELTA LIKE-4 are up-regulated secondary to hyperglycemia and activate both canonical and rapid noncanonical NOTCH1 pathways that ultimately disrupt endothelial adherens junctions in diabetic retinas by causing dissociation of vascular endothelial-cadherin from β-catenin. We further demonstrate that neutralization of NOTCH1 ligands prevents diabetes-induced retinal edema. Collectively, these results identify a fundamental process in diabetes-mediated vascular permeability and provide translational rational for targeting the NOTCH pathway (primarily JAGGED1) in conditions characterized by compromised vascular barrier function.
糖尿病性黄斑水肿是糖尿病的一种主要并发症，可导致中心视力丧失。尽管血管通透性增加与神经胶质和神经元衍生的因素有关，但对于成熟内皮细胞如何从静止状态退出并损害屏障功能的机制知之甚少。在这里，我们报告说，成熟的糖尿病视网膜中的内皮 NOTCH1 信号传导导致血管通透性增加。通过提供人和小鼠的数据，我们表明，NOTCH1 配体 JAGGED1 和 DELTA LIKE-4 由于高血糖而被上调，并激活经典和快速非经典 NOTCH1 途径，最终通过引起血管内皮钙黏蛋白从β-连环蛋白解离来破坏糖尿病视网膜中的内皮细胞黏附连接。我们进一步证明，NOTCH1 配体的中和可防止糖尿病引起的视网膜水肿。总之，这些结果确定了糖尿病介导的血管通透性中的一个基本过程，并为靶向具有血管屏障功能受损特征的条件下的 NOTCH 途径（主要是 JAGGED1）提供了转化合理性。
