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

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

doi:10.1172/jci.insight.122043

Cited by 43 publications

(49 citation statements)

References 52 publications

(75 reference statements)

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“…In contrast, Ang1 functions as an anti-permeability growth factor and promotes EC remodeling to minimize permeability [81]. Likewise, Tie2 signaling decreases vascular permeability by tightening intra-EC junctions; this effect is mediated by associations of Tie2 receptors on adjacent cells and reorganization of key adhesion molecule vascular endothelial-cadherin (VE-cadherin) complexes [82]. As examples of its critical role in regulating vascular permeability in health and disease, Tie2 activation reduces pulmonary vascular leakage during cardiopulmonary bypass in rats [83], reduces cerebrovascular permeability and stroke size in mouse models [84], and reduced renal vascular edema and transcapillary albumin flux is a mouse model of acute kidney injury [85].…”

Section: Vascular Permeabilitymentioning

confidence: 99%

“…AXT107 (Table 2) is a 20-mer synthetic peptide derived from the non-collagenous domain of collagen IV that may be a triple threat to the pathophysiology of retinal vascular diseases: suppressing ocular neovascularization, inhibiting vascular leakage, and reducing inflammation [79,92]. AXT107 targets two pathways in a single molecule: it promotes Tie2 pathway signaling [82] while blocking VEGF pathway signaling [92]. Both of these actions are mediated by AXT107's interaction with and disruption of the proteins integrin α v β 3 [82,92] and integrin α 5 β 1 [82,92,[98][99][100].…”

Section: Targeting the Tie2 Pathway For Retinal Vascular Diseases Axt107mentioning

confidence: 99%

“…AXT107 targets two pathways in a single molecule: it promotes Tie2 pathway signaling [82] while blocking VEGF pathway signaling [92]. Both of these actions are mediated by AXT107's interaction with and disruption of the proteins integrin α v β 3 [82,92] and integrin α 5 β 1 [82,92,[98][99][100].…”

Section: Targeting the Tie2 Pathway For Retinal Vascular Diseases Axt107mentioning

confidence: 99%

“…Integrins are essential for the attachment of cells to the ECM. Integrin α 5 β 1 interacts with Tie2 receptors and sequesters them at EC-ECM interface [82]. In this resting state, Ang2 is a Tie2 antagonist.…”

Section: Targeting the Tie2 Pathway For Retinal Vascular Diseases Axt107mentioning

confidence: 99%

“…The reorganization and junctional clustering of Tie2 induced by AXT107 allows Ang2, which normally functions as an antagonist of Tie2 and is an inducer of vascular leakage, to function as a strong agonist of Tie2 and a promoter of vascular integrity. Tie2 phosphorylation then activates the myriad downstream signaling pathways that promote vascular integrity and health [82,92].…”

Section: Targeting the Tie2 Pathway For Retinal Vascular Diseases Axt107mentioning

confidence: 99%

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The Tie2 signaling pathway in retinal vascular diseases: a novel therapeutic target in the eye

et al. 2020

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Background Retinal vascular diseases such as neovascular age-related macular degeneration, diabetic retinopathy and/or diabetic macular edema, and retinal vein occlusion with macular edema—share several key pathophysiologic aspects including neovascularization, vascular permeability, and inflammation. The role of vascular endothelial growth factor (VEGF) in these processes, and the therapeutic benefits of VEGF inhibition, have been well characterized. Anti-VEGF therapy is highly effective for many patients but is not uniformly effective in all patients and imposes a significant treatment burden. More recently, the role of the Tie2 signaling pathway in the pathophysiology of retinal vascular diseases has been investigated, and the Tie2 pathway represents a novel therapeutic target for these conditions. Areas covered The index review describes the Tie2 pathway and its complementary role to the VEGF pathway in the angiogenesis cascade and will summarize studies of molecules in development to therapeutically modulate the Tie2 pathway in retinal vascular diseases. Conclusions Activation of the Tie2 pathway leads to downstream signaling that promotes vascular health and stability and decreases vascular permeability and inflammation. AXT107 is a collagen IV–derived synthetic peptide with a dual mechanism of action that involves suppression of VEGF signaling and activation of the Tie2 pathway; these actions are accomplished by AXT107 binding to and disrupting different integrin, leading to blockade of the VEGF receptor and rearrangement of cellular Tie2 rendering it susceptible to Ang2 agonism. Other Tie2 agonist compounds are also in development, including faricimab and razuprotafib. Tie2 activation only modestly impacts angiogenesis on its own but significantly potentiates VEGF suppression. Co-regulation of the VEGF and Tie2 signaling pathways has the potential to improve functional and structural outcomes in eyes with retinal vascular diseases.

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Section: Vascular Permeabilitymentioning

confidence: 99%

Section: Targeting the Tie2 Pathway For Retinal Vascular Diseases Axt107mentioning

confidence: 99%

Section: Targeting the Tie2 Pathway For Retinal Vascular Diseases Axt107mentioning

confidence: 99%

Section: Targeting the Tie2 Pathway For Retinal Vascular Diseases Axt107mentioning

confidence: 99%

Section: Targeting the Tie2 Pathway For Retinal Vascular Diseases Axt107mentioning

confidence: 99%

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The Tie2 signaling pathway in retinal vascular diseases: a novel therapeutic target in the eye

et al. 2020

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Posttranslational modifications in retinal degeneration diseases: An update on the molecular basis and treatment

Yao,

Mou,

Jiang

et al. 2024

Brain-X

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Noninherited diseases and age‐associated vision loss are often associated with retinal degeneration. The retina is a postmitotic neural tissue lacking endogenous regeneration capacity. Therefore, understanding the mechanism of retinal degeneration in diseases is pivotal. Posttranslational modifications (PTMs) determine protein function during physiological and pathological processes, including signal transduction, protein localization, and protein activation. Advanced detection technologies have revealed over 400 different PTMs including acetylation, methylation, phosphorylation, ubiquitination and SUMOylation. Here, we discuss PTMs in retinal degeneration diseases to aid in our understanding of their molecular basis and suggest potential future clinical treatment.

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Exploring the Potential of Wild Olive (Acebuche) Oil as a Pharm‐Food to Prevent Ocular Hypertension and Fibrotic Events in the Retina of Hypertensive Mice

Santana‐Garrido,

Reyes‐Goya,

André

et al. 2023

Molecular Nutrition Food Res

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ScopeOur laboratory has previously described the antioxidant and anti‐inflammatory potential of a wild olive (acebuche, ACE) oil against hypertension‐associated vascular retinopathies. The current study aims to analyze the antifibrotic effect of ACE oil on the retina of hypertensive mice.Methods and resultsMice are rendered hypertensive by administration of NG‐nitro‐L‐arginine‐methyl‐ester (L‐NAME) and simultaneously subjected to dietary supplementation with ACE oil or a reference extra virgin olive oil (EVOO). Intraocular pressure (IOP) is measured by rebound tonometry, and retinal vasculature/layers are analyzed by fundus fluorescein angiography and optical coherence tomography. Different fibrosis‐related parameters are analyzed in the retina and choroid of normotensive and hypertensive mice with or without oil supplementation. Besides preventing the alterations found in hypertensive animals, including increased IOP, reduced fluorescein signal, and altered retinal layer thickness, the ACE oil‐enriched diet improves collagen metabolism by regulating the expression of major fibrotic process modulators (matrix metalloproteinases, tissue inhibitors of metalloproteinases, connective tissue growth factor, and transforming growth factor beta family).ConclusionRegular consumption of EVOO and ACE oil (with better outcomes in the latter) might help reduce abnormally high IOP values in the context of hypertension‐related retinal damage, with significant reduction in the surrounding fibrotic process.

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

Cited by 43 publications

References 52 publications

The Tie2 signaling pathway in retinal vascular diseases: a novel therapeutic target in the eye

The Tie2 signaling pathway in retinal vascular diseases: a novel therapeutic target in the eye

Posttranslational modifications in retinal degeneration diseases: An update on the molecular basis and treatment

Exploring the Potential of Wild Olive (Acebuche) Oil as a Pharm‐Food to Prevent Ocular Hypertension and Fibrotic Events in the Retina of Hypertensive Mice

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