title: BMP activity controlled by BMPER regulates the proinflammatory phenotype of endothelium.
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.
authors: Department of Cardiology, University of Freiburg, Freiburg, Germany.
authors: Thomas
authors: T
authors: Helbing
authors: René
authors: R
authors: Rothweiler
authors: Elena
authors: E
authors: Ketterer
authors: Lena
authors: L
authors: Goetz
authors: Jennifer
authors: J
authors: Heinke
authors: Sebastian
authors: S
authors: Grundmann
authors: Daniel
authors: D
authors: Duerschmied
authors: Cam
authors: C
authors: Patterson
authors: Christoph
authors: C
authors: Bode
authors: Martin
authors: M
authors: Moser
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000502:physiology; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D014657:Vasculitis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D018836:Inflammation Mediators; C517553:crossveinless 2 protein, mouse