Antagonism and synergy between extracellular BMP modulators Tsg and BMPER balance blood vessel formation

J Cell Sci. 2013 Jul 15;126(Pt 14):3082-94. doi: 10.1242/jcs.122333. Epub 2013 May 2.

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.

Keywords: Angiogenesis; BMP modulators; Endothelial cells; Signalling; Zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Vessels / cytology
  • Blood Vessels / growth & development*
  • Bone Morphogenetic Proteins / agonists
  • Bone Morphogenetic Proteins / antagonists & inhibitors
  • Carrier Proteins / metabolism*
  • Carrier Proteins / pharmacology
  • Cell Growth Processes / drug effects
  • Cell Growth Processes / genetics
  • Cells, Cultured
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Homeostasis
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / physiology*
  • Humans
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic* / drug effects
  • Neovascularization, Physiologic* / genetics
  • Oncogene Protein v-akt / metabolism
  • Proteins / genetics
  • Proteins / metabolism*
  • Proteins / pharmacology
  • RNA, Small Interfering / genetics
  • Smad Proteins / metabolism
  • Zebrafish

Substances

  • BMPER protein, human
  • Bone Morphogenetic Proteins
  • Carrier Proteins
  • Proteins
  • RNA, Small Interfering
  • Smad Proteins
  • TWSG1 protein, human
  • Oncogene Protein v-akt
  • Extracellular Signal-Regulated MAP Kinases