Differential effect of hypoxia on early endothelial-mesenchymal transition response to transforming growth beta isoforms 1 and 2

Microvasc Res. 2016 Nov:108:48-63. doi: 10.1016/j.mvr.2016.08.001. Epub 2016 Aug 5.

Abstract

Angiogenesis is essential for mammalian development and tissue homeostasis, and is involved in several pathological processes, including tumor growth and dissemination. Many factors within the tissue microenvironment are known to modulate angiogenesis, including cytokines, such as transforming growth factor beta (TGFβ), and oxygen level. TGFβ exists in three different isoforms (1, 2 and 3), all of which (albeit in different contexts) might mediate angiogenesis and are able to induce endothelial-mesenchymal transition (EndoMT), a process involved in heart development, pathologic fibrosis and, as recently reported, in angiogenesis. Low oxygen level, referred to as hypoxia, has been independently shown to induce angiogenesis, modulate TGFβ signalling and promote EndoMT. However, how these phenomena might be interconnected to drive angiogenesis is rather unexplored. To begin addressing the potential contribution of TGFβ-induced EndoMT to angiogenesis, and to explore how microenvironmental hypoxia might influence these processes, we investigated the effect of TGFβ isoforms 1 and 2 on early EndoMT response in cultured adult endothelium under standard (21 %) and hypoxic (1 %) culture conditions. Our data indicates that EndoMT-like changes, such as an increase in expression and nuclear translocation of Snail, Slug and Zeb1, and reduction of VE-cadherin expression, occur in response to TGFβ1 and/or TGFβ2 as early as 6h after stimulation and might be enhanced by hypoxia in an isoform-specific manner. Further, hypoxia enhances canonical TGFβ signalling, and appears to be a key determinant of Snail's differential involvement in endothelial cell responses to TGFβ1 versus TGFβ2.

Keywords: Angiogenesis; Endothelial cell sprouting; Endothelial–mesenchymal transition; Hypoxia; Snail; Transforming growth factor beta.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Cadherins / metabolism
  • Cattle
  • Cell Hypoxia
  • Cells, Cultured
  • Cellular Microenvironment
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Epithelial-Mesenchymal Transition / drug effects*
  • Humans
  • Kinetics
  • Neovascularization, Physiologic / drug effects*
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Interference
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / agonists
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / drug effects
  • Smad1 Protein / metabolism
  • Smad2 Protein / metabolism
  • Snail Family Transcription Factors / genetics
  • Snail Family Transcription Factors / metabolism
  • Transfection
  • Transforming Growth Factor beta1 / pharmacology*
  • Transforming Growth Factor beta2 / pharmacology*
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism

Substances

  • Antigens, CD
  • Cadherins
  • Receptors, Transforming Growth Factor beta
  • Smad1 Protein
  • Smad2 Protein
  • Snail Family Transcription Factors
  • TGFB1 protein, human
  • TGFB2 protein, human
  • Transforming Growth Factor beta1
  • Transforming Growth Factor beta2
  • Zinc Finger E-box-Binding Homeobox 1
  • cadherin 5
  • Vascular Endothelial Growth Factor Receptor-2
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I