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Circulation. 2016 Jan 26;133(4):409-21. doi: 10.1161/CIRCULATIONAHA.115.017537. Epub 2015 Dec 9.

Targeting NCK-Mediated Endothelial Cell Front-Rear Polarity Inhibits Neovascularization.

Author information

1
From 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.).
2
From 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.

Abstract

BACKGROUND:

Sprouting 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 RESULTS:

Mice 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.

CONCLUSIONS:

These data reveal a novel signal integration mechanism involving NCK1/2, ROBO1/2, and VEGFR2 that controls endothelial cell front-rear polarity during sprouting angiogenesis.

KEYWORDS:

Slit-Robo; VEGF; angiogenesis, pathologic; cell movement; cell polarity; neovascularization, pathologic; vascular biology

PMID:
26659946
PMCID:
PMC4729599
DOI:
10.1161/CIRCULATIONAHA.115.017537
[Indexed for MEDLINE]
Free PMC Article

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