A collagen IV-derived peptide disrupts α5β1 integrin and potentiates Ang2/Tie2 signaling

• Autores: Mirando, Adam C.; Shen, Jikui; Silva, Raquel Lima E.; Chu, Zenny; Sass, Nicholas C.; Lorenc, Valeria Erika; Green, Jordan J.; Campochiaro, Peter A.; Popel, Aleksander S.; Pandey, Niranjan B.
• Año de publicación: 2019
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: GROWTH FACTORS; INTEGRINS; OPHTHALMOLOGY; RETINOPATHY; VASCULAR BIOLOGY
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

The angiopoietin (Ang)/Tie2 signaling pathway is essential for maintaining vascular homeostasis, and its dysregulation is associated with several diseases. Interactions between Tie2 and α5 β1 integrin have emerged as part of this control; however, the mechanism is incompletely understood. AXT107, a collagen IV–derived peptide, has strong antipermeability activity and has enabled the elucidation of this previously undetermined mechanism. Previously, AXT107 was shown to inhibit VEGFR2 and other growth factor signaling via receptor tyrosine kinase association with specific integrins. AXT107 disrupts α5 β1 and stimulates the relocation of Tie2 and α5 to cell junctions. In the presence of Ang2 and AXT107, junctional Tie2 is activated, downstream survival signals are upregulated, F-actin is rearranged to strengthen junctions, and, as a result, endothelial junctional permeability is reduced. These data suggest that α5 β1 sequesters Tie2 in nonjunctional locations in endothelial cell membranes and that AXT107-induced disruption of α5 β1 promotes clustering of Tie2 at junctions and converts Ang2 into a strong agonist, similar to responses observed when Ang1 levels greatly exceed those of Ang2. The potentiation of Tie2 activation by Ang2 even extended to mouse models in which AXT107 induced Tie2 phosphorylation in a model of hypoxia and inhibited vascular leakage in an Ang2-overexpression transgenic model and an LPS-induced inflammation model. Because Ang2 levels are very high in ischemic diseases, such as diabetic macular edema, neovascular age-related macular degeneration, uveitis, and cancer, targeting α5 β1 with AXT107 provides a potentially more effective approach to treat these diseases.
Fil: Mirando, Adam C.. University Johns Hopkins; Estados Unidos
Fil: Shen, Jikui. University Johns Hopkins; Estados Unidos
Fil: Silva, Raquel Lima E.. University Johns Hopkins; Estados Unidos
Fil: Chu, Zenny. University Johns Hopkins; Estados Unidos
Fil: Sass, Nicholas C.. University Johns Hopkins; Estados Unidos
Fil: Lorenc, Valeria Erika. University Johns Hopkins; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Green, Jordan J.. University Johns Hopkins; Estados Unidos. AsclepiX Therapeutics; Estados Unidos
Fil: Campochiaro, Peter A.. University Johns Hopkins; Estados Unidos
Fil: Popel, Aleksander S.. University Johns Hopkins; Estados Unidos
Fil: Pandey, Niranjan B.. University Johns Hopkins; Estados Unidos. AsclepiX Therapeutics; Estados Unidos