The Multi-Kinase Inhibitor RepSox Enforces Barrier Function in the Face of Both VEGF and Cytokines
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, promo...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/9/2431 |
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| author | Lina Lietuvninkas Basma Baccouche Andrius Kazlauskas |
| author_facet | Lina Lietuvninkas Basma Baccouche Andrius Kazlauskas |
| author_sort | Lina Lietuvninkas |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T23:00:01Z |
| format | Article |
| id | doaj.art-1b352bb3117a420dbe4d05a1278843c3 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T23:00:01Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-1b352bb3117a420dbe4d05a1278843c32023-11-19T09:41:13ZengMDPI AGBiomedicines2227-90592023-08-01119243110.3390/biomedicines11092431The Multi-Kinase Inhibitor RepSox Enforces Barrier Function in the Face of Both VEGF and CytokinesLina Lietuvninkas0Basma Baccouche1Andrius Kazlauskas2Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USAThe 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.https://www.mdpi.com/2227-9059/11/9/2431RepSoxendothelial cellspermeabilitydiabetesretinopathyanti-VEGF |
| spellingShingle | Lina Lietuvninkas Basma Baccouche Andrius Kazlauskas The Multi-Kinase Inhibitor RepSox Enforces Barrier Function in the Face of Both VEGF and Cytokines Biomedicines RepSox endothelial cells permeability diabetes retinopathy anti-VEGF |
| title | The Multi-Kinase Inhibitor RepSox Enforces Barrier Function in the Face of Both VEGF and Cytokines |
| title_full | The Multi-Kinase Inhibitor RepSox Enforces Barrier Function in the Face of Both VEGF and Cytokines |
| title_fullStr | The Multi-Kinase Inhibitor RepSox Enforces Barrier Function in the Face of Both VEGF and Cytokines |
| title_full_unstemmed | The Multi-Kinase Inhibitor RepSox Enforces Barrier Function in the Face of Both VEGF and Cytokines |
| title_short | The Multi-Kinase Inhibitor RepSox Enforces Barrier Function in the Face of Both VEGF and Cytokines |
| title_sort | multi kinase inhibitor repsox enforces barrier function in the face of both vegf and cytokines |
| topic | RepSox endothelial cells permeability diabetes retinopathy anti-VEGF |
| url | https://www.mdpi.com/2227-9059/11/9/2431 |
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