A collagen IV–derived peptide disrupts α5β1 integrin and potentiates Ang2/Tie2 signaling
Adam C. Mirando, … , Aleksander S. Popel, Niranjan B. Pandey
Adam C. Mirando, … , Aleksander S. Popel, Niranjan B. Pandey
Published January 22, 2019
Citation Information: JCI Insight. 2019;4(4):e122043. https://doi.org/10.1172/jci.insight.122043.
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Research Article Ophthalmology Vascular biology

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

Abstract

The angiopoietin (Ang)/Tie2 signaling pathway is essential for maintaining vascular homeostasis, and its dysregulation is associated with several diseases. Interactions between Tie2 and α5β1 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 α5β1 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 α5β1 sequesters Tie2 in nonjunctional locations in endothelial cell membranes and that AXT107-induced disruption of α5β1 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 α5β1 with AXT107 provides a potentially more effective approach to treat these diseases.

Authors

Adam C. Mirando, Jikui Shen, Raquel Lima e Silva, Zenny Chu, Nicholas C. Sass, Valeria E. Lorenc, Jordan J. Green, Peter A. Campochiaro, Aleksander S. Popel, Niranjan B. Pandey

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Figure 7

AXT107 inhibits Ang2- and LPS-mediated vascular permeability in the mouse eye.

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AXT107 inhibits Ang2- and LPS-mediated vascular permeability in the mous...
(A–C) Representative fluorescein angiography images of mouse eyes from IRBP-rtTA/TRE-Ang2 mice with doxycycline-induced overexpression of Ang 2 in the retina given an intravitreous injection of PBS (A) or 1 μg of AXT107 (B). Compared with the normal retinal vessels seen in an untreated wild-type C57BL/6 mouse, the Ang2-overexpressing PBS-injected control shows dilated retinal vessels with extravasation of fluorescein blurring the margins of the vessels (A), while the AXT107-treated Ang2 overexpressor shows sharp vessel margins, indicating no fluorescein leakage and mild vasodilation (B). (D) Doxycycline-treated IRBP-rtTA/TRE-Ang2 mice given an intravitreous injection of 1 μg of AXT107 had a significant reduction in mean level of albumin in the vitreous compared with PBS-injected controls; n = 11; P < 0.05 by Mann-Whitney test. (E) Relative gene expression of cyclophilin and Ang2 in the retinas of mice treated with intravitreous injection of 125 ng LPS or PBS control. Fold changes were determined by ΔΔCT (n = 4 or 5). P < 0.01 by Mann-Whitney test. (F) Mean vitreous albumin level in mice with LPS-induced uveitis was significantly less in those given an intravitreous injection of 1 μg AXT107 compared with PBS-injected controls (n = 5). P < 0.01 by Mann-Whitney test.