Blood Journal
Leading the way in experimental and clinical research in hematology

BMP activity controlled by BMPER regulates the proinflammatory phenotype of endothelium

  1. Thomas Helbing1,
  2. René Rothweiler1,
  3. Elena Ketterer1,
  4. Lena Goetz1,
  5. Jennifer Heinke1,
  6. Sebastian Grundmann1,
  7. Daniel Duerschmied1,
  8. Cam Patterson2,
  9. Christoph Bode1, and
  10. Martin Moser1
  1. 1Department of Cardiology, University of Freiburg, Freiburg, Germany; and
  2. 2Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, Chapel Hill, NC

Abstract

The endothelium plays a pivotal role in vascular inflammation. Here we study bone morphogenetic protein (BMP) signaling in endothelial inflammation and in particular the role of BMPER, an extracellular BMP modulator that is important in vascular development and angiogenesis. Using the BMP antagonist dorsomorphin or BMP2 as an agonist we show that BMP signaling is essential for the inflammatory response of vascular endothelial cells as demonstrated by intravital microscopy. We found that BMPER is decreased in inflammation similar to vascular protective genes like KLF2 and eNOS. Using in vitro and in vivo models we show that BMPER is down-regulated through the TNFα-NFκB-KLF2 signaling pathway. Functionally, lack of BMPER induced by siRNA or in BMPER+/− mice confers a proinflammatory endothelial phenotype with reduced eNOS levels and enhanced expression of adhesion molecules leading to increased leukocyte adhesion and extravasation in ex vivo and in vivo experiments. Vice versa, addition of BMPER exerts endothelium protective functions and antagonizes TNFα induced inflammation. Mechanistically, we demonstrate that these effects of BMPER are dependent on BMP signaling because of enhanced NFκB activity. In conclusion, the BMP modulator BMPER is a new protective regulator of vascular inflammation that modulates leukocyte adhesion and migration in vitro and in vivo.

  • Submitted March 5, 2011.
  • Accepted July 25, 2011.
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