title: Antagonism and synergy between extracellular BMP modulators Tsg and BMPER balance blood vessel formation.
abstract: Growth and regeneration of blood vessels are crucial processes during embryonic development and in adult disease. Members of the bone morphogenetic protein (BMP) family are growth factors known to play a key role in vascular development. The BMP pathway is controlled by extracellular BMP modulators such as BMP endothelial cell precursor derived regulator (BMPER), which we reported previously acts proangiogenically on endothelial cells in a concentration-dependent manner. Here, we explore the function of other BMP modulators, especially Tsg, on endothelial cell behaviour and compare them to BMPER. In Matrigel assays, BMP modulators chordin and noggin had no stimulatory effect; however, gremlin and Tsg enhanced human umbilical vein endothelial cell (HUVEC) sprouting. As the activation dynamics of Tsg were similar to those of BMPER, we further investigated the proangiogenic effect of Tsg on endothelial cells. Tsg enhanced endothelial cell ingrowth in the mouse Matrigel plug assay as well as HUVEC sprouting, migration and proliferation in vitro, dependent on Akt, Erk and Smad signalling pathway activation in a concentration-dependent manner. Surprisingly, silencing of Tsg also increased HUVEC sprouting, migration and proliferation, which is again associated with Akt, Erk and Smad signalling pathway activation. Furthermore, we reveal that Tsg and BMPER interfere with each other to enhance proangiogenic events. However, in vivo the presence of Tsg as well as of BMPER is mandatory for regular development of the zebrafish vasculature. Taken together, our results suggest that BMPER and Tsg maintain a fine-tuned equilibrium that controls BMP pathway activity and is necessary for vascular cell homeostasis.
authors: Heart Center, Freiburg University, Cardiology and Angiology I, 79106 Freiburg, Germany. Jennifer.Heinke@universitaets-herzzentrum.de
authors: Jennifer
authors: J
authors: Heinke
authors: Maria
authors: M
authors: Juschkat
authors: Anne
authors: A
authors: Charlet
authors: Leonie
authors: L
authors: Mnich
authors: Thomas
authors: T
authors: Helbing
authors: Christoph
authors: C
authors: Bode
authors: Cam
authors: C
authors: Patterson
authors: Martin
authors: M
authors: Moser
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000254:growth & development*; D019485:Bone Morphogenetic Proteins / Q000819:agonists / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000378:metabolism* / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006706:Homeostasis; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D015027:Zebrafish
chemical_list: C476724:BMPER protein, human; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D051785:Smad Proteins; C576635:TWSG1 protein, human; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Angiogenesis; BMP modulators; Endothelial cells; Signalling; Zebrafish