|
|
血管内皮细胞钙粘蛋白在糖尿病视网膜病变中的作用研究进展
|
Abstract:
糖尿病视网膜病变(Diabetic retinopathy, DR)是成人致盲的主要原因之一，目前认为VEGF在DR的进展中占据重要地位，却缺乏对其上下游环节的研究，而血管内皮细胞钙粘蛋白(Vascular endothelial cell cadherin, VE-cadherin)作为VEGF介导的信号通路的下游环节与视网膜血管通透性改变、视网膜屏障破坏及新生血管形成密切相关。本文分析了VE-cadherin在维持DR血管结构和功能稳定、血管形成、炎症反应中起到的重要作用，发现通过调节其表达和磷酸化状态，可能有助于防止血管渗漏和新生血管形成，因此我们推测VE-cadherin可能是治疗DR的潜在靶点。
Diabetic retinopathy (DR) is the major cause of severe vision loss in adults. Currently, VEGF is recognized to play a pivotal role in the progression of DR, yet there is a lack of research on its upstream and downstream mechanisms. Vascular endothelial cell cadherin (VE-cadherin), as a downstream component of VEGF-mediated signaling pathways, is closely associated with alterations in retinal vascular permeability, disruption of the retinal barrier, and neovascularization. This paper analyzes the crucial role of VE-cadherin in maintaining the stability of vascular structure and function, angiogenesis and inflammatory responses in DR. It is also found that by modulating its expression and phosphorylation status, it may help prevent vascular leakage and neovascularization. Therefore, we hypothesize that VE-cadherin could be a potential therapeutic target for the treatment of DR.
| [1] | International Diabetes Federation (2022) Shape the Future of Diabetes at the IDF World Diabetes Congress 2022. Diabetes Research and Clinical Practice, 187, Article 109909. https://doi.org/10.1016/j.diabres.2022.109909 |
| [2] | Yin, L., Zhang, D., Ren, Q., Su, X. and Sun, Z. (2020) Prevalence and Risk Factors of Diabetic Retinopathy in Diabetic Patients. Medicine, 99, e19236. https://doi.org/10.1097/md.0000000000019236 |
| [3] | Suzuki, S., Sano, K. and Tanihara, H. (1991) Diversity of the Cadherin Family: Evidence for Eight New Cadherins in Nervous Tissue. Cell Regulation, 2, 261-270. https://doi.org/10.1091/mbc.2.4.261 |
| [4] | Nan, W., He, Y., Wang, S. and Zhang, Y. (2023) Molecular Mechanism of Ve-Cadherin in Regulating Endothelial Cell Behaviour during Angiogenesis. Frontiers in Physiology, 14, Article 1234104. https://doi.org/10.3389/fphys.2023.1234104 |
| [5] | Gavard, J. and Gutkind, J.S. (2006) VEGF Controls Endothelial-Cell Permeability by Promoting the Β-Arrestin-Dependent Endocytosis of Ve-Cadherin. Nature Cell Biology, 8, 1223-1234. https://doi.org/10.1038/ncb1486 |
| [6] | Liu, D., Xu, H., Zhang, C., Xie, H., Yang, Q., Li, W., et al. (2020) Erythropoietin Maintains Ve-Cadherin Expression and Barrier Function in Experimental Diabetic Retinopathy via Inhibiting VEGF/VEGFR2/Src Signaling Pathway. Life Sciences, 259, Article 118273. https://doi.org/10.1016/j.lfs.2020.118273 |
| [7] | Dragoni, S., Caridi, B., Karatsai, E., Burgoyne, T., Sarker, M.H. and Turowski, P. (2021) AMP-Activated Protein Kinase Is a Key Regulator of Acute Neurovascular Permeability. Journal of Cell Science, 134, jcs253179. https://doi.org/10.1242/jcs.253179 |
| [8] | Richards, M., Pal, S., Sjöberg, E., Martinsson, P., Venkatraman, L. and Claesson-Welsh, L. (2021) Intra-Vessel Heterogeneity Establishes Enhanced Sites of Macromolecular Leakage Downstream of Laminin Α5. Cell Reports, 35, Article 109268. https://doi.org/10.1016/j.celrep.2021.109268 |
| [9] | Rudraraju, M., Narayanan, S.P. and Somanath, P.R. (2021) Distinct Mechanisms of Human Retinal Endothelial Barrier Modulation in Vitro by Mediators of Diabetes and Uveitis. Life, 12, Article 33. https://doi.org/10.3390/life12010033 |
| [10] | Zhang, R., Li, R. and Tang, Y. (2019) Soluble Vascular Endothelial Cadherin: A Promising Marker of Critical Illness? Critical Care, 23, Article No. 57. https://doi.org/10.1186/s13054-019-2343-7 |
| [11] | Ozer, F., Tokuc, E.O., Albayrak, M.G.B., Akpinar, G., Kasap, M. and Karabas, V.L. (2022) Comparison of before versus after Intravitreal Bevacizumab Injection, Growth Factor Levels and Fibrotic Markers in Vitreous Samples from Patients with Proliferative Diabetic Retinopathy. Graefe’s Archive for Clinical and Experimental Ophthalmology, 260, 1899-1906. https://doi.org/10.1007/s00417-021-05515-3 |
| [12] | Deng, H., Wang, S., Wang, X., Li, L., Xie, F., Zeng, Z., et al. (2019) Puerarin Protects against LPS-Induced Vascular Endothelial Cell Hyperpermeability via Preventing Downregulation of Endothelial Cadherin. Inflammation, 42, 1504-1510. https://doi.org/10.1007/s10753-019-01014-0 |
| [13] | 孙文娟, 纪风涛, 李永蓉. 雷珠单抗对糖尿病视网膜病变患者手术前后血清VE-cadherin和bFGF的影响[J]. 河北医学, 2020, 26(8): 1237-1241. |
| [14] | 王苏涵, 张乐颖, 秦婷婷. VEGF在糖尿病视网膜病变破坏血-视网膜屏障机制中的研究新进展[J]. 国际眼科杂志, 2024, 24(8): 1260-1265. |
| [15] | Orsenigo, F., Giampietro, C., Ferrari, A., Corada, M., Galaup, A., Sigismund, S., et al. (2012) Phosphorylation of Ve-Cadherin Is Modulated by Haemodynamic Forces and Contributes to the Regulation of Vascular Permeability in Vivo. Nature Communications, 3, Article No. 1208. https://doi.org/10.1038/ncomms2199 |
| [16] | Smith, R.O., Ninchoji, T., Gordon, E., André, H., Dejana, E., Vestweber, D., et al. (2020) Vascular Permeability in Retinopathy Is Regulated by VEGFR2 Y949 Signaling to Ve-Cadherin. E Life, 9, e54056. https://doi.org/10.7554/elife.54056 |
| [17] | Sun, W., An, X., Zhang, Y., Zhao, X., Sun, Y., Yang, C., et al. (2023) The Ideal Treatment Timing for Diabetic Retinopathy: The Molecular Pathological Mechanisms Underlying Early-Stage Diabetic Retinopathy Are a Matter of Concern. Frontiers in Endocrinology, 14, Article 1270145. https://doi.org/10.3389/fendo.2023.1270145 |
| [18] | 索龙, 曹国凡. 周细胞在新生血管性眼病中的作用研究进展[J]. 国际眼科杂志, 2021, 22(1): 79-82. |
| [19] | Sheng, X., Zhang, C., Zhao, J., Xu, J., Zhang, P., Ding, Q., et al. (2024) Microvascular Destabilization and Intricated Network of the Cytokines in Diabetic Retinopathy: From the Perspective of Cellular and Molecular Components. Cell & Bioscience, 14, Article No. 85. |
| [20] | Zhang, C., Gu, L., Xie, H., Liu, Y., Huang, P., Zhang, J., et al. (2024) Glucose Transport, Transporters and Metabolism in Diabetic Retinopathy. Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease, 1870, Article 166995. https://doi.org/10.1016/j.bbadis.2023.166995 |
| [21] | Garrett, J.P., Lowery, A.M., Adam, A.P., Kowalczyk, A.P. and Vincent, P.A. (2017) Regulation of Endothelial Barrier Function by P120-Catenin∙Ve-Cadherin Interaction. Molecular Biology of the Cell, 28, 85-97. https://doi.org/10.1091/mbc.e16-08-0616 |
| [22] | Zhang, L., Ma, L., Li, J., Lei, J., Chen, J. and Yu, C. (2021) Ve-Cadherin N-Glycosylation Modified by N-Acetylglucosaminyltransferase V Regulates Ve-Cadherin-β-Catenin Interaction and Monocyte Adhesion. Experimental Physiology, 106, 1869-1877. https://doi.org/10.1113/ep089617 |
| [23] | Grimsley-Myers, C.M., Isaacson, R.H., Cadwell, C.M., Campos, J., Hernandes, M.S., Myers, K.R., et al. (2020) Ve-cadherin Endocytosis Controls Vascular Integrity and Patterning during Development. Journal of Cell Biology, 219, e201909081. https://doi.org/10.1083/jcb.201909081 |
| [24] | 刘爽. 炎性细胞因子在糖尿病视网膜病变发病中的作用[J]. 国际眼科纵览, 2022, 46(4): 327-332. |
| [25] | Haidari, M., Zhang, W., Willerson, J.T. and Dixon, R.A. (2014) Disruption of Endothelial Adherens Junctions by High Glucose Is Mediated by Protein Kinase C-Β-Dependent Vascular Endothelial Cadherin Tyrosine Phosphorylation. Cardiovascular Diabetology, 13, Article No. 105. https://doi.org/10.1186/1475-2840-13-105 |
| [26] | Arif, N., Zinnhardt, M., Nyamay’Antu, A., Teber, D., Brückner, R., Schaefer, K., et al. (2021) PECAM-1 Supports Leukocyte Diapedesis by Tension-Dependent Dephosphorylation of Ve-Cadherin. The EMBO Journal, 40, 1-20. https://doi.org/10.15252/embj.2020106113 |
| [27] | Vestweber, D. (2015) How Leukocytes Cross the Vascular Endothelium. Nature Reviews Immunology, 15, 692-704. https://doi.org/10.1038/nri3908 |
| [28] | Li, R., Li, L., Liu, Y., Tang, Y. and Zhang, R. (2019) Ve-Cadherin Regulates Migration Inhibitory Factor Synthesis and Release. Inflammation Research, 68, 877-887. https://doi.org/10.1007/s00011-019-01270-8 |
| [29] | Smith, R.O., Ninchoji, T., et al. (2020) Vascular Permeability in Retinopathy Is Regulated by VEGFR2 Y949 Signaling to VE-Cadherin. https://pubmed.ncbi.nlm.nih.gov/32312382/ |
| [30] | Wakasugi, R., Suzuki, K. and Kaneko-Kawano, T. (2024) Molecular Mechanisms Regulating Vascular Endothelial Permeability. International Journal of Molecular Sciences, 25, Article 6415. https://doi.org/10.3390/ijms25126415 |
| [31] | Chrifi, I., Louzao-Martinez, L., et al. (2019) CMTM4 Regulates Angiogenesis by Promoting Cell Surface Recycling of VE-Cadherin to Endothelial Adherens Junctions. https://pubmed.ncbi.nlm.nih.gov/30097810/ |
| [32] | Bentley, K., Franco, C.A., Philippides, A., Blanco, R., Dierkes, M., Gebala, V., et al. (2014) The Role of Differential Ve-Cadherin Dynamics in Cell Rearrangement during Angiogenesis. Nature Cell Biology, 16, 309-321. https://doi.org/10.1038/ncb2926 |
| [33] | Li, J., Xie, R., Jiang, F., Li, Y., Zhu, Y., Liu, Z., et al. (2021) Tumor Necrosis Factor Ligand-Related Molecule 1A Maintains Blood-Retinal Barrier via Modulating SHP-1-Src-VE-Cadherin Signaling in Diabetic Retinopathy. The FASEB Journal, 35, e22008. https://doi.org/10.1096/fj.202100807rr |
| [34] | Ting, K.K., Zhao, Y., Shen, W., Coleman, P., Yam, M., Chan-Ling, T., et al. (2018) Therapeutic Regulation of Ve-Cadherin with a Novel Oligonucleotide Drug for Diabetic Eye Complications Using Retinopathy Mouse Models. Diabetologia, 62, 322-334. https://doi.org/10.1007/s00125-018-4770-4 |
