Normal vitreous promotes angiogenesis via activation of Axl

Wu, Wenyi; Xia, Xiaobo; Tang, Luosheng; Yao, Fei; Xu, Hong‐Ji; Lei, Hetian

doi:10.1096/fj.201903105r

Cited by 7 publications

(12 citation statements)

References 35 publications

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“…Tumor necrosis factor alpha (TNF-α) and interferon gamma (IFNγ) show higher concentrations in vitreous PDR in rats compared to controls but show lower concentrations in the corresponding serum [65]. It has even been suggested through an animal model that the "normal vitreous" may be pro-angiogenic (with cell migration and proliferation enhancement) through phosphoinositide 3-kinase/protein kinase B (P13K/Akt) signaling via the receptor tyrosine kinase anexelekto (Ak1) activation, as shown using the bovine vitreous and human retinal microvascular endothelial cells [66]. These findings in animal biology help to reshape the ideas of what cytokines and their associated cascades might mean in the human eye.…”

Section: Animal Modelsmentioning

confidence: 99%

The Vitreous Ecosystem in Diabetic Retinopathy: Insight into the Patho-Mechanisms of Disease

Iyer

Lagrew

Tillit

et al. 2021

IJMS

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Diabetic retinopathy is one of the leading causes of blindness in the world with the incidence of disease ever-increasing worldwide. The vitreous humor represents an extensive and complex interactive arena for cytokines in the diabetic eye. In recent decades, there has been significant progress in understanding this environment and its implications in disease pathophysiology. In this review, we investigate the vitreous ecosystem in diabetic retinopathy at the molecular level. Areas of concentration include: the current level of knowledge of growth factors, cytokine and chemokine mediators, and lipid-derived metabolites in the vitreous. We discuss the molecular patho-mechanisms of diabetic retinopathy based upon current vitreous research.

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Section: Animal Modelsmentioning

confidence: 99%

The Vitreous Ecosystem in Diabetic Retinopathy: Insight into the Patho-Mechanisms of Disease

Iyer

Lagrew

Tillit

et al. 2021

IJMS

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“…Inhibition of Axl with a pharmacological inhibitor suppressed retinal angiogenesis in a mouse model of oxygen-induced retinopathy ( 6 ). To study if this finding was related to a clinical significance, we investigated if Gas6 was enriched in vitreous from patients with PDR by ELISA.…”

Section: Resultsmentioning

confidence: 99%

“…Subsequently, we evaluated the effect of PDR vitreous on angiogenesis in an in-vitro model of a tube formation assay ( 6 ). As shown in Figures 2F,G , PDR vitreous heightened the ability of HRECs in forming tubes, suggesting that the signaling pathway of Gas6/Axl might play an important role in these PDR vitreous-enhanced cellular events intrinsic to angiogenesis.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously reported that normal bovine vitreous is also able to activate Axl for engaging activation and angiogenesis of Akt ( 6 ). In this study, the vitreous from patients with PDR shows a similar effect to normal bovine vitreous on in-vitro angiogenesis; however, PDR vitreous is obviously more relevant to pathophysiological conditions and, thus, these novel findings may provide a significant clue to develop novel approaches to prevent or cure diabetes-related retinal angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, Axl null mice respond poorly to VEGF-A-induced vascular permeability and angiogenesis ( 3 ). We previously showed that the normal bovine vitreous promotes endothelial cell proliferation and migration via Axl activation ( 6 ); however, whether Axl was activated in epiretinal fibrovascular membranes from patients with PDR remained elusive and the Axl role in human retinal vascular endothelial cells (HRECs) stimulated by PDR also needs to be clarified; for these answers, it will improve our understanding of the underlining mechanisms of pathogenesis of PDR and advance the development of additional effective treatment strategies for PDR.…”

Section: Introductionmentioning

confidence: 99%

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Axl Is Essential for in-vitro Angiogenesis Induced by Vitreous From Patients With Proliferative Diabetic Retinopathy

Meng

et al. 2021

Front. Med.

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Proliferative diabetic retinopathy (PDR), characterized mainly with abnormal epiretinal angiogenesis forming fibrovascular membranes (FVMs), threatens vision of people with diabetes; FVMs consist of extracellular matrix and a variety of cell types including vascular endothelial cells. Axl, one of receptor tyrosine kinases, can be activated indirectly by vascular endothelial growth factor-A (VEGF-A) via an intracellular route for promoting angiogenesis. In this study, we revealed that growth arrest-specific protein 6 (Gas6), a specific ligand of Axl, was elevated in vitreous from patients with PDR and that Axl was activated in FVMs from patients with PDR. In addition, we demonstrated that in cultured human retinal microvascular endothelial cells (HRECs), Axl inhibition via suppression of Axl expression with Clustered Regularly Interspaced Short Palindromic Repeats/ CRISPR-associated protein 9 or through inactivation with its specific inhibitor R428 blocked PDR vitreous-induced Akt activation and proliferation of HRECs. Furthermore, PDR vitreous-heightened migration and tube formation of HRECs were also blunted by restraining Axl. These results indicate that in the pathogenesis of PDR, Axl can be activated by Gas6 binding directly and by VEGF-A via an intracellular route indirectly, suggesting that Axl plays a pivotal role in the development of PDR and that Axl inhibition shows a bright promise for PDR therapy.

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Mass spectrometry analysis of phosphotyrosine‐containing proteins

Zhan

2023

Mass Spectrometry Reviews

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Tyrosine phosphorylation is a crucial posttranslational modification that is involved in various aspects of cell biology and often has functions in cancers. It is necessary not only to identify the specific phosphorylation sites but also to quantify their phosphorylation levels under specific pathophysiological conditions. Because of its high sensitivity and accuracy, mass spectrometry (MS) has been widely used to identify endogenous and synthetic phosphotyrosine proteins/peptides across a range of biological systems. However, phosphotyrosine‐containing proteins occur in extremely low abundance and they degrade easily, severely challenging the application of MS. This review highlights the advances in both quantitative analysis procedures and enrichment approaches to tyrosine phosphorylation before MS analysis and reviews the differences among phosphorylation, sulfation, and nitration of tyrosine residues in proteins. In‐depth insights into tyrosine phosphorylation in a wide variety of biological systems will offer a deep understanding of how signal transduction regulates cellular physiology and the development of tyrosine phosphorylation‐related drugs as cancer therapeutics.

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Normal vitreous promotes angiogenesis via activation of Axl

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 7 publications

References 35 publications

The Vitreous Ecosystem in Diabetic Retinopathy: Insight into the Patho-Mechanisms of Disease

The Vitreous Ecosystem in Diabetic Retinopathy: Insight into the Patho-Mechanisms of Disease

Axl Is Essential for in-vitro Angiogenesis Induced by Vitreous From Patients With Proliferative Diabetic Retinopathy

Mass spectrometry analysis of phosphotyrosine‐containing proteins

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