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Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature

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Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. / Shen, Jikui; Frye, Maike; Lee, Bonnie L; Reinardy, Jessica L; McClung, Joseph M; Ding, Kun; Kojima, Masashi; Xia, Huiming; Seidel, Christopher; Lima e Silva, Raquel; Dong, Aling; Hackett, Sean F; Wang, Jiangxia; Howard, Brian W; Vestweber, Dietmar; Kontos, Christopher D; Peters, Kevin G; Campochiaro, Peter A.

in: J CLIN INVEST, Jahrgang 124, Nr. 10, 10.2014, S. 4564-76.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Shen, J, Frye, M, Lee, BL, Reinardy, JL, McClung, JM, Ding, K, Kojima, M, Xia, H, Seidel, C, Lima e Silva, R, Dong, A, Hackett, SF, Wang, J, Howard, BW, Vestweber, D, Kontos, CD, Peters, KG & Campochiaro, PA 2014, 'Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature', J CLIN INVEST, Jg. 124, Nr. 10, S. 4564-76. https://doi.org/10.1172/JCI74527

APA

Shen, J., Frye, M., Lee, B. L., Reinardy, J. L., McClung, J. M., Ding, K., Kojima, M., Xia, H., Seidel, C., Lima e Silva, R., Dong, A., Hackett, S. F., Wang, J., Howard, B. W., Vestweber, D., Kontos, C. D., Peters, K. G., & Campochiaro, P. A. (2014). Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. J CLIN INVEST, 124(10), 4564-76. https://doi.org/10.1172/JCI74527

Vancouver

Shen J, Frye M, Lee BL, Reinardy JL, McClung JM, Ding K et al. Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. J CLIN INVEST. 2014 Okt;124(10):4564-76. https://doi.org/10.1172/JCI74527

Bibtex

@article{38d04b3ac713435496d9ecdf7f26ad34,
title = "Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature",
abstract = "Retinal and choroidal neovascularization (NV) and vascular leakage contribute to visual impairment in several common ocular diseases. The angiopoietin/TIE2 (ANG/TIE2) pathway maintains vascular integrity, and negative regulators of this pathway are potential therapeutic targets for these diseases. Here, we demonstrated that vascular endothelial-protein tyrosine phosphatase (VE-PTP), which negatively regulates TIE2 activation, is upregulated in hypoxic vascular endothelial cells, particularly in retinal NV. Intraocular injection of an anti-VE-PTP antibody previously shown to activate TIE2 suppressed ocular NV. Furthermore, a small-molecule inhibitor of VE-PTP catalytic activity (AKB-9778) activated TIE2, enhanced ANG1-induced TIE2 activation, and stimulated phosphorylation of signaling molecules in the TIE2 pathway, including AKT, eNOS, and ERK. In mouse models of neovascular age-related macular degeneration, AKB-9778 induced phosphorylation of TIE2 and strongly suppressed NV. Ischemia-induced retinal NV, which is relevant to diabetic retinopathy, was accentuated by the induction of ANG2 but inhibited by AKB-9778, even in the presence of high levels of ANG2. AKB-9778 also blocked VEGF-induced leakage from dermal and retinal vessels and prevented exudative retinal detachments in double-transgenic mice with high expression of VEGF in photoreceptors. These data support targeting VE-PTP to stabilize retinal and choroidal blood vessels and suggest that this strategy has potential for patients with a wide variety of retinal and choroidal vascular diseases. ",
keywords = "Aniline Compounds/pharmacology, Animals, Catalysis, Cell Hypoxia, Choroid/blood supply, Eye/blood supply, Human Umbilical Vein Endothelial Cells, Humans, Hypoxia, Macular Degeneration, Mice, Mice, Transgenic, Oxygen/metabolism, Phosphorylation, Receptor, TIE-2/metabolism, Receptor-Like Protein Tyrosine Phosphatases, Class 3/metabolism, Retinal Vessels/pathology, Signal Transduction, Sulfonic Acids/pharmacology, Vascular Endothelial Growth Factor A/metabolism",
author = "Jikui Shen and Maike Frye and Lee, {Bonnie L} and Reinardy, {Jessica L} and McClung, {Joseph M} and Kun Ding and Masashi Kojima and Huiming Xia and Christopher Seidel and {Lima e Silva}, Raquel and Aling Dong and Hackett, {Sean F} and Jiangxia Wang and Howard, {Brian W} and Dietmar Vestweber and Kontos, {Christopher D} and Peters, {Kevin G} and Campochiaro, {Peter A}",
year = "2014",
month = oct,
doi = "10.1172/JCI74527",
language = "English",
volume = "124",
pages = "4564--76",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "10",

}

RIS

TY - JOUR

T1 - Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature

AU - Shen, Jikui

AU - Frye, Maike

AU - Lee, Bonnie L

AU - Reinardy, Jessica L

AU - McClung, Joseph M

AU - Ding, Kun

AU - Kojima, Masashi

AU - Xia, Huiming

AU - Seidel, Christopher

AU - Lima e Silva, Raquel

AU - Dong, Aling

AU - Hackett, Sean F

AU - Wang, Jiangxia

AU - Howard, Brian W

AU - Vestweber, Dietmar

AU - Kontos, Christopher D

AU - Peters, Kevin G

AU - Campochiaro, Peter A

PY - 2014/10

Y1 - 2014/10

N2 - Retinal and choroidal neovascularization (NV) and vascular leakage contribute to visual impairment in several common ocular diseases. The angiopoietin/TIE2 (ANG/TIE2) pathway maintains vascular integrity, and negative regulators of this pathway are potential therapeutic targets for these diseases. Here, we demonstrated that vascular endothelial-protein tyrosine phosphatase (VE-PTP), which negatively regulates TIE2 activation, is upregulated in hypoxic vascular endothelial cells, particularly in retinal NV. Intraocular injection of an anti-VE-PTP antibody previously shown to activate TIE2 suppressed ocular NV. Furthermore, a small-molecule inhibitor of VE-PTP catalytic activity (AKB-9778) activated TIE2, enhanced ANG1-induced TIE2 activation, and stimulated phosphorylation of signaling molecules in the TIE2 pathway, including AKT, eNOS, and ERK. In mouse models of neovascular age-related macular degeneration, AKB-9778 induced phosphorylation of TIE2 and strongly suppressed NV. Ischemia-induced retinal NV, which is relevant to diabetic retinopathy, was accentuated by the induction of ANG2 but inhibited by AKB-9778, even in the presence of high levels of ANG2. AKB-9778 also blocked VEGF-induced leakage from dermal and retinal vessels and prevented exudative retinal detachments in double-transgenic mice with high expression of VEGF in photoreceptors. These data support targeting VE-PTP to stabilize retinal and choroidal blood vessels and suggest that this strategy has potential for patients with a wide variety of retinal and choroidal vascular diseases.

AB - Retinal and choroidal neovascularization (NV) and vascular leakage contribute to visual impairment in several common ocular diseases. The angiopoietin/TIE2 (ANG/TIE2) pathway maintains vascular integrity, and negative regulators of this pathway are potential therapeutic targets for these diseases. Here, we demonstrated that vascular endothelial-protein tyrosine phosphatase (VE-PTP), which negatively regulates TIE2 activation, is upregulated in hypoxic vascular endothelial cells, particularly in retinal NV. Intraocular injection of an anti-VE-PTP antibody previously shown to activate TIE2 suppressed ocular NV. Furthermore, a small-molecule inhibitor of VE-PTP catalytic activity (AKB-9778) activated TIE2, enhanced ANG1-induced TIE2 activation, and stimulated phosphorylation of signaling molecules in the TIE2 pathway, including AKT, eNOS, and ERK. In mouse models of neovascular age-related macular degeneration, AKB-9778 induced phosphorylation of TIE2 and strongly suppressed NV. Ischemia-induced retinal NV, which is relevant to diabetic retinopathy, was accentuated by the induction of ANG2 but inhibited by AKB-9778, even in the presence of high levels of ANG2. AKB-9778 also blocked VEGF-induced leakage from dermal and retinal vessels and prevented exudative retinal detachments in double-transgenic mice with high expression of VEGF in photoreceptors. These data support targeting VE-PTP to stabilize retinal and choroidal blood vessels and suggest that this strategy has potential for patients with a wide variety of retinal and choroidal vascular diseases.

KW - Aniline Compounds/pharmacology

KW - Animals

KW - Catalysis

KW - Cell Hypoxia

KW - Choroid/blood supply

KW - Eye/blood supply

KW - Human Umbilical Vein Endothelial Cells

KW - Humans

KW - Hypoxia

KW - Macular Degeneration

KW - Mice

KW - Mice, Transgenic

KW - Oxygen/metabolism

KW - Phosphorylation

KW - Receptor, TIE-2/metabolism

KW - Receptor-Like Protein Tyrosine Phosphatases, Class 3/metabolism

KW - Retinal Vessels/pathology

KW - Signal Transduction

KW - Sulfonic Acids/pharmacology

KW - Vascular Endothelial Growth Factor A/metabolism

U2 - 10.1172/JCI74527

DO - 10.1172/JCI74527

M3 - SCORING: Journal article

C2 - 25180601

VL - 124

SP - 4564

EP - 4576

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 10

ER -