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NCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathy

Author

Listed:
  • Alexandre Dubrac

    (Yale University School of Medicine)

  • Steffen E. Künzel

    (Yale University School of Medicine)

  • Sandrine H. Künzel

    (Yale University School of Medicine)

  • Jinyu Li

    (Yale University School of Medicine)

  • Rachana Radhamani Chandran

    (Yale University School of Medicine)

  • Kathleen Martin

    (Yale University School of Medicine)

  • Daniel M. Greif

    (Yale University School of Medicine)

  • Ralf H. Adams

    (Max Planck Institute for Molecular Biomedicine)

  • Anne Eichmann

    (Yale University School of Medicine
    Paris Cardiovascular Research Center
    Yale University School of Medicine)

Abstract

Pericytes are mural cells that surround capillaries and control angiogenesis and capillary barrier function. During sprouting angiogenesis, endothelial cell-derived platelet-derived growth factor-B (PDGF-B) regulates pericyte proliferation and migration via the platelet-derived growth factor receptor-β (PDGFRβ). PDGF-B overexpression has been associated with proliferative retinopathy, but the underlying mechanisms remain poorly understood. Here we show that abnormal, α-SMA-expressing pericytes cover angiogenic sprouts and pathological neovascular tufts (NVTs) in a mouse model of oxygen-induced retinopathy. Genetic lineage tracing demonstrates that pericytes acquire α-SMA expression during NVT formation. Pericyte depletion through inducible endothelial-specific knockout of Pdgf-b decreases NVT formation and impairs revascularization. Inactivation of the NCK1 and NCK2 adaptor proteins inhibits pericyte migration by preventing PDGF-B-induced phosphorylation of PDGFRβ at Y1009 and PAK activation. Loss of Nck1 and Nck2 in mural cells prevents NVT formation and vascular leakage and promotes revascularization, suggesting PDGFRβ-Y1009/NCK signaling as a potential target for the treatment of retinopathies.

Suggested Citation

  • Alexandre Dubrac & Steffen E. Künzel & Sandrine H. Künzel & Jinyu Li & Rachana Radhamani Chandran & Kathleen Martin & Daniel M. Greif & Ralf H. Adams & Anne Eichmann, 2018. "NCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathy," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05926-7
    DOI: 10.1038/s41467-018-05926-7
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