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Targeting NCK-Mediated Endothelial Cell Front-Rear Polarity Inhibits Neovascularization.
Dubrac, Alexandre; Genet, Gael; Ola, Roxana; Zhang, Feng; Pibouin-Fragner, Laurence; Han, Jinah; Zhang, Jiasheng; Thomas, Jean-Léon; Chedotal, Alain; Schwartz, Martin A; Eichmann, Anne.
Afiliação
  • Dubrac A; 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
  • Genet G; 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
  • Ola R; 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
  • Zhang F; 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
  • Pibouin-Fragner L; 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
  • Han J; 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
  • Zhang J; 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
  • Thomas JL; 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
  • Chedotal A; 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
  • Schwartz MA; 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
  • Eichmann A; 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
Circulation ; 133(4): 409-21, 2016 Jan 26.
Article em En | MEDLINE | ID: mdl-26659946
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Polaridade Celular / Deleção de Genes / Proteínas Oncogênicas / Neovascularização Fisiológica / Células Endoteliais / Proteínas Adaptadoras de Transdução de Sinal Limite: Animals / Humans Idioma: En Revista: Circulation Ano de publicação: 2016 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Polaridade Celular / Deleção de Genes / Proteínas Oncogênicas / Neovascularização Fisiológica / Células Endoteliais / Proteínas Adaptadoras de Transdução de Sinal Limite: Animals / Humans Idioma: En Revista: Circulation Ano de publicação: 2016 Tipo de documento: Article