Specialized Retinal Endothelial Cells Modulate Blood-Retina Barrier in Diabetic Retinopathy

被引:4
|
作者
Yao, Xuyang [1 ,2 ]
Zhao, Ziyan [3 ]
Zhang, Wenhui [3 ]
Liu, Ruixin [3 ]
Ni, Tianwen [1 ,2 ]
Cui, Bohao [4 ]
Lei, Yi [4 ]
Du, Jie [5 ]
Ai, Ding [3 ]
Jiang, Hongfeng [5 ]
Lv, Huizhen [1 ,2 ,3 ]
Li, Xiaorong [1 ,2 ]
机构
[1] Tianjin Med Univ, Eye Inst, Tianjin Key Lab Retinal Funct & Dis, Tianjin Branch,Natl Clin Res Ctr Ocular Dis, Tianjin, Peoples R China
[2] Tianjin Med Univ, Tianjin Med Univ Eye Hosp, Sch Optometry, Tianjin, Peoples R China
[3] Tianjin Med Univ, Dept Physiol & Pathophysiol, Tianjin, Peoples R China
[4] Tianjin Med Univ Gen Hosp, Dept Ophthalmol, Tianjin, Peoples R China
[5] Capital Med Univ, Beijing Anzhen Hosp, Expt Res Ctr, Beijing Inst Heart Lung & Blood Vessel Dis, Beijing, Peoples R China
基金
中国国家自然科学基金;
关键词
SPHINGOLIPID METABOLISM; ANGIOGENESIS; INFLAMMATION; CERAMIDE; ATLAS;
D O I
10.2337/db23-0368
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Endothelial cells (EC) play essential roles in retinal vascular homeostasis. This study aimed to characterize retinal EC heterogeneity and functional diversity using single-cell RNA sequencing. Systematic analysis of cellular compositions and cell-cell interaction networks identified a unique EC cluster with high inflammatory gene expression in diabetic retina; sphingolipid metabolism is a prominent aspect correlated with changes in retinal function. Among sphingolipid-related genes, alkaline ceramidase 2 (ACER2) showed the most significant increase. Plasma samples of patients with nonproliferative diabetic retinopathy (NPDR) with diabetic macular edema (DME) or without DME (NDME) and active proliferative DR (PDR) were collected for mass spectrometry analysis. Metabolomic profiling revealed that the ceramide levels were significantly elevated in NPDR-NDME/DME and further increased in active PDR compared with control patients. In vitro analyses showed that ACER2 overexpression retarded endothelial barrier breakdown induced by ceramide, while silencing of ACER2 further disrupted the injury. Moreover, intravitreal injection of the recombinant ACER2 adeno-associated virus rescued diabetes-induced vessel leakiness, inflammatory response, and neurovascular disease in diabetic mouse models. Together, this study revealed a new diabetes-specific retinal EC population and a negative feedback regulation pathway that reduces ceramide content and endothelial dysfunction by upregulating ACER2 expression. These findings provide insights into cell-type targeted interventions for diabetic retinopathy.
引用
收藏
页码:225 / 236
页数:12
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