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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalJCI insight
Volume4
Issue number4
DOIs
StatePublished - Feb 21 2019

Fingerprint

Integrins
Collagen
Peptides
Blood Vessels
Angiopoietins
Intercellular Junctions
Macular Edema
Uveitis
Macular Degeneration
Receptor Protein-Tyrosine Kinases
Cluster Analysis
Actins
Permeability
Intercellular Signaling Peptides and Proteins
Homeostasis
Endothelial Cells
Phosphorylation
Cell Membrane
Inflammation
Neoplasms

Keywords

  • growth factors
  • Integrins
  • Ophthalmology
  • Retinopathy
  • Vascular Biology

Cite this

A collagen IV-derived peptide disrupts α5β1 integrin and potentiates Ang2/Tie2 signaling. / Mirando, Adam C.; Shen, Jikui; Formica, Raquel; Chu, Zenny; Sass, Nicholas C.; Lorenc, Valeria E.; Green, Jordan; Campochiaro, Peter A; Popel, Aleksander S; Pandey, Niranjan.

In: JCI insight, Vol. 4, No. 4, 21.02.2019.

Research output: Contribution to journalArticle

@article{c6997de4c4604ff9815ea0ab6ea7d274,
title = "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.",
keywords = "growth factors, Integrins, Ophthalmology, Retinopathy, Vascular Biology",
author = "Mirando, {Adam C.} and Jikui Shen and Raquel Formica and Zenny Chu and Sass, {Nicholas C.} and Lorenc, {Valeria E.} and Jordan Green and Campochiaro, {Peter A} and Popel, {Aleksander S} and Niranjan Pandey",
year = "2019",
month = "2",
day = "21",
doi = "10.1172/jci.insight.122043",
language = "English (US)",
volume = "4",
journal = "JCI insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "4",

}

TY - JOUR

T1 - A collagen IV-derived peptide disrupts α5β1 integrin and potentiates Ang2/Tie2 signaling

AU - Mirando, Adam C.

AU - Shen, Jikui

AU - Formica, Raquel

AU - Chu, Zenny

AU - Sass, Nicholas C.

AU - Lorenc, Valeria E.

AU - Green, Jordan

AU - Campochiaro, Peter A

AU - Popel, Aleksander S

AU - Pandey, Niranjan

PY - 2019/2/21

Y1 - 2019/2/21

N2 - 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.

AB - 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.

KW - growth factors

KW - Integrins

KW - Ophthalmology

KW - Retinopathy

KW - Vascular Biology

UR - http://www.scopus.com/inward/record.url?scp=85062086720&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062086720&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.122043

DO - 10.1172/jci.insight.122043

M3 - Article

VL - 4

JO - JCI insight

JF - JCI insight

SN - 2379-3708

IS - 4

ER -