The Antiangiogenic Effects of Integrin α5β1 Inhibitor (ATN-161) In Vitro and In Vivo

Wang, Wenqiu; Wang, Fenghua; Lu, Fei; Xu, Shan; Hu, Weiting; Huang, Jiannan; Gu, Qing; Sun, Xiaodong

doi:10.1167/iovs.10-7097

Cited by 40 publications

(41 citation statements)

References 47 publications

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“…Because endothelial cell migration and tube formation constitute an important process in blood vessel formation and both the Ang1-Tie2 system 15 and integrin α5β1 16 are key regulators of the angiogenic process, we tested whether integrin α5β1-Ang1/Tie2 receptor cross-talk regulates the migration and tube formation of BECs.…”

Section: Resultsmentioning

confidence: 99%

“…The expression of α5β1 integrin is upregulated in response to angiogenic factors 21 , and α5β1 integrin has previously been shown to be involved in mediating cell migration and tube formation in human choroidal endothelial cells 16 . In this study, we further found that Ang1 induces cell migration and tube formation of BECs after OGD, but this effect was attenuated by diminishing the levels of α5 integrin in BECs.…”

Section: Discussionmentioning

confidence: 99%

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Integrin α5β1-Ang1/Tie2 receptor cross-talk regulates brain endothelial cell responses following cerebral ischemia

et al. 2018

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We have previously demonstrated that in response to cerebral ischemia (CI), the growth factor angiopoietin-1 (Ang1) and α5β1 integrin are both induced in cerebral vessels, which likely provide positive signals driving the endogenous angiogenic response and vascular protection after CI. However, the precise relationship between endothelial Ang1 and α5β1 integrin after CI remains poorly understood. Here, we investigated the effects of the interaction between the Ang1/Tie2 system and α5β1 integrin on brain endothelial cells (BECs) under cerebral ischemic conditions in vivo and in vitro. Immunofluorescence analysis demonstrated that integrin α5β1 co-localized with Tie2/phosphorylated Tie2 on cerebral vessels in the penumbra. The in vitro study showed that oxygen–glucose deprivation/restoration (OGD/R) induced the expression of the Ang1 receptor Tie2 on BECs in a manner similar to that for integrin α5 and Ang1 in response to OGD/R, accompanied by increased activation of Tie2 and its downstream effectors focal adhesion kinase (FAK) and Akt. Knockdown of α5 integrin markedly suppressed OGD/R-induced Tie2 receptor activation in BECs, while in contrast, priming BECs with Ang1 promoted the expression of α5 integrin as well as the Tie2 downstream transcription factor Ets-1 in OGD-treated BECs. In line with this, Ets-1 knockdown significantly attenuated Ang1-mediated upregulation of α5 integrin. Functionally, Ang1 induced cell migration and tube formation of BECs after OGD, but this effect was inhibited by diminishment of the levels of α5 integrin in BECs. Taken together, our data indicate that the Ang1/Tie2 system cross-talks with integrin α5β1 in BECs after CI, which may contribute to the endogenous angiogenic vascular protective response following CI.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Integrin α5β1-Ang1/Tie2 receptor cross-talk regulates brain endothelial cell responses following cerebral ischemia

et al. 2018

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“…28,29 Sections from within 200 lm of the optic disc were chosen for processing because they were assumed to have a similar thickness. 30 Briefly, after deparaffinization and rehydration, sections were treated with sodium citrate buffer (pH 6.0, 10 minutes) and blocking buffer (10% normal goat serum, 0.05% Triton X-100 in PBS; 1 hour, room temperature).…”

Section: Hematoxylin and Eosin (Hande) Stainingmentioning

confidence: 99%

MicroRNA Expression Patterns Involved in Amyloid Beta–Induced Retinal Degeneration

Huang

Sun

Wang

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Citation: Huang P, Sun J, Wang F, et al. MicroRNA expression patterns involved in amyloid beta-induced retinal degeneration. Invest Ophthalmol Vis Sci. 2017;58:172658: -173558: . DOI: 10.1167 PURPOSE. Dry age-related macular degeneration (AMD) is characterized by the accumulation of drusen under Bruch's membrane, and amyloid beta (Ab) is speculated to be one of the key pathologic factors. While the detrimental effects of Ab on retinas have been widely explored, Ab-induced epigenetic regulatory changes have yet to be fully investigated. We therefore aimed to identify the microRNA (miRNA) expression profiles in an Ab-induced mouse model of retinal degeneration.METHODS. C57BL/6 mice were intravitreally injected with Ab 1-40 or PBS and the eye tissues were collected for hematoxylin and eosin (H&E) staining, apoptosis immunofluorescence staining, and miRNA profiling. After filtering, 10 miRNAs and their target genes were chosen for quantitative RT-PCR (qRT-PCR) confirmations. Pathway analyses were employed for further bioinformatic analyses.RESULTS. Hematoxylin and eosin-stained sections of retinal pigment epithelium (RPE)/neural retina tissue demonstrated degenerative alterations, and immunofluorescence testing revealed apoptosis within the retina after Ab treatments. MicroRNA profiling revealed 61 miRNAs that were differentially expressed between the model and the control group. Among these, 38 miRNAs were upregulated (fold change > 1.5, P < 0.05) and 23 miRNAs were downregulated (fold change < 0.667, P < 0.05). Five of the 10 selected miRNAs (miR-142, miR-216, miR-155, miR-223, and miR-433) as well as several key target genes (CFH, IGF-1R, c-MET, and ABCA1) were confirmed by qRT-PCR analyses.CONCLUSIONS. Our study is the first to profile the miRNA expression patterns and suggests that Ab accumulation could lead to relevant biochemical alternations such as complement activation, barrier impairment, apoptosis, and positive feedback of Ab production.

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“…Targeting α5β1 integrin with ATN-161 in combination with radiotherapy enhanced apoptosis of breast cancer cells grown in 3D culture [91]. ATN-161 proved also efficient to block choroidal neovascularisation [152]. Phase I trial of ATN-161 indicated that it was well tolerated in patients with solid tumors and that one third of patients manifested prolonged stable disease.…”

Section: Integrin α5β1 Antagonistsmentioning

confidence: 99%

Integrin α5β1, the Fibronectin Receptor, as a Pertinent Therapeutic Target in Solid Tumors

Schaffner

Ray

Dontenwill

2013

Cancers

172

161

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Integrins are transmembrane heterodimeric proteins sensing the cell microenvironment and modulating numerous signalling pathways. Changes in integrin expression between normal and tumoral cells support involvement of specific integrins in tumor progression and aggressiveness. This review highlights the current knowledge about α5β1 integrin, also called the fibronectin receptor, in solid tumors. We summarize data showing that α5β1 integrin is a pertinent therapeutic target expressed by tumoral neovessels and tumoral cells. Although mainly evaluated in preclinical models, α5β1 integrin merits interest in particular in colon, breast, ovarian, lung and brain tumors where its overexpression is associated with a poor prognosis for patients. Specific α5β1 integrin antagonists will be listed that may represent new potential therapeutic agents to fight defined subpopulations of particularly aggressive tumors.

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The Antiangiogenic Effects of Integrin α5β1 Inhibitor (ATN-161) In Vitro and In Vivo

Abstract: Integrin α5β1 inhibition by ATN-161 may be a promising alternative therapy for CNV-related angiogenesis. In addition, SD-OCT technology allows excellent visualization of experimentally induced CNV in vivo.

Cited by 40 publications

References 47 publications

Integrin α5β1-Ang1/Tie2 receptor cross-talk regulates brain endothelial cell responses following cerebral ischemia

Integrin α5β1-Ang1/Tie2 receptor cross-talk regulates brain endothelial cell responses following cerebral ischemia

MicroRNA Expression Patterns Involved in Amyloid Beta–Induced Retinal Degeneration

Integrin α5β1, the Fibronectin Receptor, as a Pertinent Therapeutic Target in Solid Tumors

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