Lietuvninkas Lina, Baccouche Basma, Kazlauskas Andrius
Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA.
Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA.
Biomedicines. 2023 Aug 31;11(9):2431. doi: 10.3390/biomedicines11092431.
The therapeutic benefit provided by anti-vascular endothelial growth factor (VEGF) for patients with vision-threatening conditions such as diabetic retinopathy (DR) demonstrates the important role of VEGF in this affliction. Cytokines, which can be elevated in the vitreous of patients with DR, promote leakage of retinal blood vessels, and may also contribute to pathology, especially in those patients for whom anti-VEGF does not provide adequate benefit. In this in vitro study using primary human retinal endothelial cells, we compared anti-VEGF with the (transforming growth factor beta) TGFβ receptor inhibitor RepSox (RS) for their ability to enforce barrier function in the face of VEGF, cytokines, and the combination of both. RS was superior to anti-VEGF because it prevented permeability in response to VEGF, cytokines, and their combination, whereas anti-VEGF was effective against VEGF alone. The inhibitory effect of RS was associated with suppression of both agonist-induced pore formation and disorganization of adherens junctions. RS-mediated inhibition of the TGFβ pathway and increased expression of claudin-5 did not adequately explain how RS stabilized the endothelial cell barrier. Finally, RS not only prevented barrier relaxation, but also completely or partially reclosed a barrier relaxed with tumor necrosis factor α (TNF α) or VEGF, respectively. These studies demonstrate that RS stabilized the endothelial barrier in the face of both cytokines and VEGF, and thereby identify RS as a therapeutic that has the potential to overcome permeability driven by multiple agonists that play a role in the pathology of DR.
抗血管内皮生长因子（VEGF）为患有诸如糖尿病视网膜病变（DR）等威胁视力疾病的患者带来的治疗益处，证明了VEGF在这种疾病中的重要作用。细胞因子在DR患者的玻璃体中可能升高，可促进视网膜血管渗漏，也可能导致病变，尤其是在那些抗VEGF治疗效果不佳的患者中。在这项使用原代人视网膜内皮细胞的体外研究中，我们比较了抗VEGF与（转化生长因子β）TGFβ受体抑制剂RepSox（RS）在面对VEGF、细胞因子以及两者联合作用时增强屏障功能的能力。RS优于抗VEGF，因为它能防止对VEGF、细胞因子及其联合作用产生的通透性增加，而抗VEGF仅对单独的VEGF有效。RS的抑制作用与抑制激动剂诱导的孔隙形成和黏附连接的紊乱有关。RS介导的对TGFβ途径的抑制和紧密连接蛋白5表达的增加并不能充分解释RS如何稳定内皮细胞屏障。最后，RS不仅防止了屏障松弛，还分别完全或部分重新封闭了因肿瘤坏死因子α（TNFα）或VEGF而松弛的屏障。这些研究表明，RS在面对细胞因子和VEGF时能稳定内皮屏障，从而确定RS作为一种治疗方法，有可能克服由多种在DR病理过程中起作用的激动剂驱动的通透性增加。
