ArticleCirculation2016
Targeting NCK-Mediated Endothelial Cell Front-Rear Polarity Inhibits Neovascularization.
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Article in Circulation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers, 1 of them a synthesis that pooled it.
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55citing papers in PubMed, 1 pooled it
2.4field-weighted citation impact, top 12% of its field
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Who cites it
55 citing papers in PubMed, 1 synthesis or guideline pooled it, 84 citations in OpenAlex.
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- CNTN6 Modulates Slit-Robo Signaling in Cortical GABAergic Interneuron Migration.Neuroscience bulletin · 2026Article
- CD47 stabilizes ROBO2 to regulate glioblastoma progression by preventing ITCH-mediated ubiquitination.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Discovery of a first-in-class SLIT2 binder disrupting the SLIT2/ROBO1 axisRSC medicinal chemistry · 2025Article
- Optimization and development of a high-throughput TR-FRET screening assay for SLIT2/ROBO1 interaction.SLAS discovery : advancing life sciences R & D · 2025Article
- Identifying potential biomarkers in the hippocampus of chronic fatigue syndrome rats treated with moxibustion at Zusanli (ST36): a proteomics study.Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan · 2025Article
- Vascular FLRT2 regulates venous-mediated angiogenic expansion and CNS barriergenesis.Nature communications · 2024Article
- Monoclonal antibodies that block Roundabout 1 and 2 signaling target pathological ocular neovascularization through myeloid cells.Science translational medicine · 2024Article
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- Induced Endothelial Cell Cycle Arrest Prevents Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia.Circulation · 2024Article
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- Distinct Requirements for Adaptor Proteins NCK1 and NCK2 in Mammary Gland Development.Journal of mammary gland biology and neoplasia · 2023Article
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- Exploiting synergistic effect of CO/NO gases for soft tissue transplantation using a hydrogel patch.Nature communications · 2023Article
- Potential diagnostic value of N1LR and SNHG1 in acute myocardial infarction.BMC medical genomics · 2023Article
- Expanding the phenome and variome of the ROBO-SLIT pathway in congenital heart defects: toward improving the genetic testing yield of CHD.Journal of translational medicine · 2023Article
- Actin cytoskeleton in angiogenesis.Biology open · 2022Review
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Alexandre DubracFrom Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT (A.D., G.G., R.O., F.Z., J.H., J.Z., J.-L.T., A.E.); INSERM U1050, Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris (L.P.-F., A.E.); Department of Neurology, Yale University School of Medicine, New Haven, CT (J.-L.T.); Institut du Cerveau et de la Moelle, Inserm, Université Pierre et Marie Curie, Paris, France (J.-L.T.); Sorbonne Universités, UPMC Universités Paris 06, INSERM, UMR-S968, CNRS, UMR-7210, Institut de la Vision, France (A.C.); Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT (M.A.S.); and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT (A.E.).
Gael GenetFrom Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT (A.D., G.G., R.O., F.Z., J.H., J.Z., J.-L.T., A.E.); INSERM U1050, Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris (L.P.-F., A.E.); Department of Neurology, Yale University School of Medicine, New Haven, CT (J.-L.T.); Institut du Cerveau et de la Moelle, Inserm, Université Pierre et Marie Curie, Paris, France (J.-L.T.); Sorbonne Universités, UPMC Universités Paris 06, INSERM, UMR-S968, CNRS, UMR-7210, Institut de la Vision, France (A.C.); Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT (M.A.S.); and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT (A.E.).
Roxana OlaFrom Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT (A.D., G.G., R.O., F.Z., J.H., J.Z., J.-L.T., A.E.); INSERM U1050, Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris (L.P.-F., A.E.); Department of Neurology, Yale University School of Medicine, New Haven, CT (J.-L.T.); Institut du Cerveau et de la Moelle, Inserm, Université Pierre et Marie Curie, Paris, France (J.-L.T.); Sorbonne Universités, UPMC Universités Paris 06, INSERM, UMR-S968, CNRS, UMR-7210, Institut de la Vision, France (A.C.); Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT (M.A.S.); and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT (A.E.).
Feng ZhangFrom Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT (A.D., G.G., R.O., F.Z., J.H., J.Z., J.-L.T., A.E.); INSERM U1050, Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris (L.P.-F., A.E.); Department of Neurology, Yale University School of Medicine, New Haven, CT (J.-L.T.); Institut du Cerveau et de la Moelle, Inserm, Université Pierre et Marie Curie, Paris, France (J.-L.T.); Sorbonne Universités, UPMC Universités Paris 06, INSERM, UMR-S968, CNRS, UMR-7210, Institut de la Vision, France (A.C.); Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT (M.A.S.); and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT (A.E.).
Laurence Pibouin-FragnerFrom Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT (A.D., G.G., R.O., F.Z., J.H., J.Z., J.-L.T., A.E.); INSERM U1050, Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris (L.P.-F., A.E.); Department of Neurology, Yale University School of Medicine, New Haven, CT (J.-L.T.); Institut du Cerveau et de la Moelle, Inserm, Université Pierre et Marie Curie, Paris, France (J.-L.T.); Sorbonne Universités, UPMC Universités Paris 06, INSERM, UMR-S968, CNRS, UMR-7210, Institut de la Vision, France (A.C.); Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT (M.A.S.); and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT (A.E.).
Jinah HanFrom Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT (A.D., G.G., R.O., F.Z., J.H., J.Z., J.-L.T., A.E.); INSERM U1050, Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris (L.P.-F., A.E.); Department of Neurology, Yale University School of Medicine, New Haven, CT (J.-L.T.); Institut du Cerveau et de la Moelle, Inserm, Université Pierre et Marie Curie, Paris, France (J.-L.T.); Sorbonne Universités, UPMC Universités Paris 06, INSERM, UMR-S968, CNRS, UMR-7210, Institut de la Vision, France (A.C.); Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT (M.A.S.); and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT (A.E.).
Jiasheng ZhangFrom Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT (A.D., G.G., R.O., F.Z., J.H., J.Z., J.-L.T., A.E.); INSERM U1050, Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris (L.P.-F., A.E.); Department of Neurology, Yale University School of Medicine, New Haven, CT (J.-L.T.); Institut du Cerveau et de la Moelle, Inserm, Université Pierre et Marie Curie, Paris, France (J.-L.T.); Sorbonne Universités, UPMC Universités Paris 06, INSERM, UMR-S968, CNRS, UMR-7210, Institut de la Vision, France (A.C.); Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT (M.A.S.); and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT (A.E.).
Jean-Léon ThomasFrom Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT (A.D., G.G., R.O., F.Z., J.H., J.Z., J.-L.T., A.E.); INSERM U1050, Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris (L.P.-F., A.E.); Department of Neurology, Yale University School of Medicine, New Haven, CT (J.-L.T.); Institut du Cerveau et de la Moelle, Inserm, Université Pierre et Marie Curie, Paris, France (J.-L.T.); Sorbonne Universités, UPMC Universités Paris 06, INSERM, UMR-S968, CNRS, UMR-7210, Institut de la Vision, France (A.C.); Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT (M.A.S.); and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT (A.E.).
Alain ChedotalFrom Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT (A.D., G.G., R.O., F.Z., J.H., J.Z., J.-L.T., A.E.); INSERM U1050, Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris (L.P.-F., A.E.); Department of Neurology, Yale University School of Medicine, New Haven, CT (J.-L.T.); Institut du Cerveau et de la Moelle, Inserm, Université Pierre et Marie Curie, Paris, France (J.-L.T.); Sorbonne Universités, UPMC Universités Paris 06, INSERM, UMR-S968, CNRS, UMR-7210, Institut de la Vision, France (A.C.); Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT (M.A.S.); and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT (A.E.).
Martin A SchwartzFrom Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT (A.D., G.G., R.O., F.Z., J.H., J.Z., J.-L.T., A.E.); INSERM U1050, Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris (L.P.-F., A.E.); Department of Neurology, Yale University School of Medicine, New Haven, CT (J.-L.T.); Institut du Cerveau et de la Moelle, Inserm, Université Pierre et Marie Curie, Paris, France (J.-L.T.); Sorbonne Universités, UPMC Universités Paris 06, INSERM, UMR-S968, CNRS, UMR-7210, Institut de la Vision, France (A.C.); Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT (M.A.S.); and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT (A.E.).
Anne EichmannFrom Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT (A.D., G.G., R.O., F.Z., J.H., J.Z., J.-L.T., A.E.); INSERM U1050, Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris (L.P.-F., A.E.); Department of Neurology, Yale University School of Medicine, New Haven, CT (J.-L.T.); Institut du Cerveau et de la Moelle, Inserm, Université Pierre et Marie Curie, Paris, France (J.-L.T.); Sorbonne Universités, UPMC Universités Paris 06, INSERM, UMR-S968, CNRS, UMR-7210, Institut de la Vision, France (A.C.); Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT (M.A.S.); and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT (A.E.). anne.eichmann@yale.edu.
Yale University · US
Funding
Vascular Training GrantT32HL007950 · NHLBI · YALE UNIVERSITY · PI JEFFREY R. BENDER, Daniel Greif · 2000 to 2026
$9.6MIntegrins in the Endothelial Response to Fluid Shear StressR01HL075092 · NHLBI · YALE UNIVERSITY · PI SCHWARTZ, MARTIN A · 2004 to 2019
$5.1MNeurovascular RegenerationR01EB016629 · NIBIB · YALE UNIVERSITY · PI HIRSCHI, KAREN KEMPER · 2014 to 2018
$4.8MTargeting endothelial migration to prevent neovascularizationR01HL125811 · NHLBI · YALE UNIVERSITY · PI EICHMANN, ANNE CHRISTINE · 2015 to 2025
$4.1MNovel approaches to manipulate sprouting angiogenesisR01EY025979 · NEI · YALE UNIVERSITY · PI EICHMANN, ANNE CHRISTINE · 2015 to 2019
$1.9MNEI NIH HHS 1R01 EY025979-01NEI NIH HHS R01 EY025979NHLBI NIH HHS R01 HL075092NHLBI NIH HHS R01 HL125811NHLBI NIH HHS T32 HL007950NIBIB NIH HHS R01 EB016629PHS HHS 1R01HLI125811
Abstract
backgroundSprouting angiogenesis is a key process driving blood vessel growth in ischemic tissues and an important drug target in a number of diseases, including wet macular degeneration and wound healing. Endothelial cells forming the sprout must develop front-rear polarity to allow sprout extension. The adaptor proteins Nck1 and 2 are known regulators of cytoskeletal dynamics and polarity, but their function in angiogenesis is poorly understood. Here, we show that the Nck adaptors are required for endothelial cell front-rear polarity and migration downstream of the angiogenic growth factors VEGF-A and Slit2. METHODS AND
resultsMice carrying inducible, endothelial-specific Nck1/2 deletions fail to develop front-rear polarized vessel sprouts and exhibit severe angiogenesis defects in the postnatal retina and during embryonic development. Inactivation of NCK1 and 2 inhibits polarity by preventing Cdc42 and Pak2 activation by VEGF-A and Slit2. Mechanistically, NCK binding to ROBO1 is required for both Slit2- and VEGF-induced front-rear polarity. Selective inhibition of polarized endothelial cell migration by targeting Nck1/2 prevents hypersprouting induced by Notch or Bmp signaling inhibition, and pathological ocular neovascularization and wound healing, as well.
conclusionsThese data reveal a novel signal integration mechanism involving NCK1/2, ROBO1/2, and VEGFR2 that controls endothelial cell front-rear polarity during sprouting angiogenesis.
Indexed as
Gene DeletionAdaptor Proteins, Signal TransducingAmino Acid SequenceAnimalsCell PolarityEndothelial CellsGene TargetingHEK293 CellsHumansHuman Umbilical Vein Endothelial CellsMiceMice, KnockoutMolecular Sequence DataNeovascularization, PhysiologicOncogene ProteinsAdaptor Proteins, Signal TransducingNck2 protein, mouseNck proteinOncogene Proteinsangiogenesis, pathologiccell movementcell polarityneovascularization, pathologicSlit-Robovascular biologyVEGF
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