Antagonism and synergy between extracellular BMP modulators Tsg and BMPER to balance blood vessel formation
- Authors
- Heinke, J., Juschkat, M., Charlet, A., Mnich, L., Helbing, T., Bode, C., Patterson, C., and Moser, M.
- ID
- ZDB-PUB-130605-21
- Date
- 2013
- Source
- Journal of Cell Science 126(Pt 14): 3082-94 (Journal)
- Registered Authors
- Keywords
- none
- 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
- PubMed
- 23641068 Full text @ J. Cell Sci.
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 to act proangiogenic on endothelial cells in a concentration-dependent manner. Here, we explore the function of other BMP modulators and 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 Tsg displayed similar activation dynamics as 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.