Urokinase-type plasminogen activator (uPA) promotes angiogenesis by attenuating Proline-rich homeodomain protein (PRH) transcription factor activity and de-repressing vascular endothelial growth factor (VEGF) receptor expression

Victoria Stepanova, Padma-Sheela Jayaraman, Sergei V Zaitsev, Tatiana Lebedeva, Khalil Bdeir, Rachael Kershaw, Kelci R Holman, Yelena V Parfyonova, Ekaterina V Semina, Irina B Beloglazova, Vsevolod A Tkachuk, Douglas B Cines

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31 Citations (Scopus)
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Abstract

Urokinase-type plasminogen activator (uPA) regulates angiogenesis and vascular permeability through proteolytic degradation of extracellular matrix and intracellular signaling initiated upon its binding to uPAR/CD87 and other cell surface receptors. Here, we describe an additional mechanism by which uPA regulates angiogenesis. Ex-vivo VEGF-induced vascular sprouting from Matrigel-embedded aortic rings isolated from uPA knockout (uPA-/-) mice was impaired compared with vessels emanating from wild-type mice. Endothelial cells (ECs) isolated from uPA-/- mice show less proliferation and migration in response to VEGF than their wild type counterparts or uPA-/- ECs in which expression of wild type uPA had been restored. We reported previously that uPA is transported from cell surface receptors to nuclei through a mechanism that requires its kringle domain. Intranuclear uPA modulates gene transcription by binding to a subset of transcription factors. Here we report that wild type single-chain uPA, but not uPA variants incapable of nuclear transport, increases the expression of cell surface VEGF receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2) by translocating to the nuclei of ECs. Intranuclear single chain uPA binds directly to and interferes with the function of the transcription factor Hematopoietically-Expressed Homeodomain protein or Proline-Rich Homeodomain protein (HHEX/PRH), which thereby lose their physiologic capacity to repress the activity of vehgr1 and vegfr2 gene promoters. These studies identify uPA-dependent de-repression of vegfr1 and vegfr2 gene transcription through binding to HHEX/PRH as a novel mechanism by which uPA mediates the pro-angiogenic effects of VEGF and identify a potential new target for control of pathologic angiogenesis.

Original languageEnglish
Pages (from-to)15029-15045
JournalJournal of Biological Chemistry
Volume291
Issue number29
Early online date4 May 2016
DOIs
Publication statusPublished - 15 Jul 2016

Keywords

  • angiogenesis
  • urokinase plasminogen activator
  • VEGF Receptors
  • PRH/HHEX transcription factor
  • vascular endothelial growth factor (VEGF)
  • vascular biology
  • nuclear translocation
  • endothelial cell

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