From the Department of Biochemistry (N.A., P.S.).
University of Montreal, Quebec, Canada; and Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec, Canada (N.A., C.V., N.P., C.L.G., P.S., B.L.).
Arterioscler Thromb Vasc Biol. 2018 Aug;38(8):1821-1836. doi: 10.1161/ATVBAHA.118.310733.
Objective- Diabetic macular edema is a major cause of visual impairment. It is caused by blood-retinal barrier breakdown that leads to vascular hyperpermeability. Current therapeutic approaches consist of retinal photocoagulation or targeting VEGF (vascular endothelial growth factor) to limit vascular leakage. However, long-term intravitreal use of anti-VEGFs is associated with potential safety issues, and the identification of alternative regulators of vascular permeability may provide safer therapeutic options. The vascular specific BMP (bone morphogenetic protein) receptor ALK1 (activin-like kinase receptor type I) and its circulating ligand BMP9 have been shown to be potent vascular quiescence factors, but their role in the context of microvascular permeability associated with hyperglycemia has not been evaluated. Approach and Results- We investigated Alk1 signaling in hyperglycemic endothelial cells and assessed whether BMP9/Alk1 signaling could modulate vascular permeability. We show that high glucose concentrations impair Alk1 signaling, both in cultured endothelial cells and in a streptozotocin model of mouse diabetes mellitus. We observed that Alk1 signaling participates in the maintenance of vascular barrier function, as Alk1 haploinsufficiency worsens the vascular leakage observed in diabetic mice. Conversely, sustained delivery of BMP9 by adenoviral vectors significantly decreased the loss of retinal barrier function in diabetic mice. Mechanistically, we demonstrate that Alk1 signaling prevents VEGF-induced phosphorylation of VE-cadherin and induces the expression of occludin, thus strengthening vascular barrier functions. Conclusions- From these data, we suggest that by preventing retinal vascular permeability, BMP9 could serve as a novel therapeutic agent for diabetic macular edema.
目的-糖尿病性黄斑水肿是视力损害的主要原因。它是由导致血管通透性增加的血视网膜屏障破坏引起的。目前的治疗方法包括视网膜光凝或靶向 VEGF（血管内皮生长因子）以限制血管渗漏。然而，长期玻璃体内使用抗 VEGF 与潜在的安全问题相关，因此寻找血管通透性的替代调节剂可能提供更安全的治疗选择。血管特异性 BMP（骨形态发生蛋白）受体 ALK1（激活素样激酶受体 I 型）及其循环配体 BMP9 已被证明是有效的血管静止因子，但它们在与高血糖相关的微血管通透性背景下的作用尚未得到评估。方法和结果-我们研究了高血糖环境下内皮细胞中的 Alk1 信号，并评估了 BMP9/Alk1 信号是否可以调节血管通透性。我们发现高葡萄糖浓度会损害培养的内皮细胞和链脲佐菌素诱导的小鼠糖尿病模型中的 Alk1 信号。我们观察到 Alk1 信号参与维持血管屏障功能，因为 Alk1 单倍不足会加重糖尿病小鼠中观察到的血管渗漏。相反，通过腺病毒载体持续递送 BMP9 可显著降低糖尿病小鼠视网膜屏障功能的丧失。在机制上，我们证明 Alk1 信号可防止 VEGF 诱导的 VE-钙粘蛋白磷酸化，并诱导 occludin 的表达，从而增强血管屏障功能。结论-从这些数据中，我们认为 BMP9 通过防止视网膜血管通透性增加，可作为糖尿病性黄斑水肿的新型治疗剂。
