Limits...
Blood flow boosts BMP signaling to keep vessels in shape

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Bone morphogenic proteins (BMPs) and blood flow regulate vascular remodeling and homeostasis. In this issue, Baeyens et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201603106) show that blood flow sensitizes endothelial cells to BMP9 signaling by triggering Alk1/ENG complexing to suppress cell proliferation and to recruit mural cells, thereby establishing endothelial quiescence.

No MeSH data available.


Related in: MedlinePlus

Blood flow promotes ALK1/ENG association to increase BMP9 sensitivity. In the absence of blood flow and at low concentrations of BMP9, ALK1 is not able to phosphorylate its downstream effectors SMAD1/5/8. However, in the presence of blood flow, shear stress promotes the association of ENG with ALK1, which decreases the endothelial EC50 toward BMP9. Thus, blood flow promotes ALK1 tyrosine kinase activity and phosphorylation of SMAD1/5/8 at low concentrations of BMP9. The overall effect of the synergy between blood flow and BMP signaling is the inhibition of cell proliferation and the recruitment of mural cells, promoting vessel stabilization and quiescence. SMADs are likely the key mediators of these effects; however, this relationship is not yet firmly established.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC5037414&req=5

fig1: Blood flow promotes ALK1/ENG association to increase BMP9 sensitivity. In the absence of blood flow and at low concentrations of BMP9, ALK1 is not able to phosphorylate its downstream effectors SMAD1/5/8. However, in the presence of blood flow, shear stress promotes the association of ENG with ALK1, which decreases the endothelial EC50 toward BMP9. Thus, blood flow promotes ALK1 tyrosine kinase activity and phosphorylation of SMAD1/5/8 at low concentrations of BMP9. The overall effect of the synergy between blood flow and BMP signaling is the inhibition of cell proliferation and the recruitment of mural cells, promoting vessel stabilization and quiescence. SMADs are likely the key mediators of these effects; however, this relationship is not yet firmly established.

Mentions: In contrast, Baeyens et al. (2016) demonstrate that blood flow sensitizes endothelial cells toward BMP9, changing its EC50 from 60 pg/ml in no-flow conditions to 3.5 pg/ml when exposed to 1.2 Pa of shear stress. Interestingly, ALK1 and ENG appear to have different roles during BMP9 flow signaling. Whereas ALK1 is required for any BMP9 signaling, ENG seems to be particularly critical for flow-dependent sensitization to low BMP9 concentrations. This finding fits well with the inducible mouse models of HHT and may explain why Alk1 deletion has a stronger impact in AVM formation than deletion of Eng. Mechanistically, Baeyens et al. (2016) propose that blood flow enables a physical interaction between ALK1 and ENG, which is responsible for the increased sensitivity to BMP9. Indeed, the authors were able to coimmunoprecipitate ALK1 and ENG when endothelial cells are exposed to flow but not in the presence of BMP9 alone. Collectively, the results by Baeyens et al. (2016) argue that enhanced BMP signaling is the key mediator for endothelial quiescence in response to flow (Fig. 1). Knockdown of either ALK1 or ENG reversed two known but critical effects of shear stress on endothelial cells: suppression of proliferation and mural cell recruitment (Baeyens et al., 2016). Intriguingly, in mice where ALK1 was randomly deleted in a subpopulation of labeled endothelial cells, only the ALK1-deficient cells proliferated more and showed decreased mural cell coverage. Given that endothelial cell proliferation and reduced recruitment of mural cells have previously been suggested to drive AVM formation, the newly identified convergence of blood flow and BMP signaling on these processes provides a molecular mechanism for the development of HHT lesions when ALK1 or ENG are defective.


Blood flow boosts BMP signaling to keep vessels in shape
Blood flow promotes ALK1/ENG association to increase BMP9 sensitivity. In the absence of blood flow and at low concentrations of BMP9, ALK1 is not able to phosphorylate its downstream effectors SMAD1/5/8. However, in the presence of blood flow, shear stress promotes the association of ENG with ALK1, which decreases the endothelial EC50 toward BMP9. Thus, blood flow promotes ALK1 tyrosine kinase activity and phosphorylation of SMAD1/5/8 at low concentrations of BMP9. The overall effect of the synergy between blood flow and BMP signaling is the inhibition of cell proliferation and the recruitment of mural cells, promoting vessel stabilization and quiescence. SMADs are likely the key mediators of these effects; however, this relationship is not yet firmly established.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5037414&req=5

fig1: Blood flow promotes ALK1/ENG association to increase BMP9 sensitivity. In the absence of blood flow and at low concentrations of BMP9, ALK1 is not able to phosphorylate its downstream effectors SMAD1/5/8. However, in the presence of blood flow, shear stress promotes the association of ENG with ALK1, which decreases the endothelial EC50 toward BMP9. Thus, blood flow promotes ALK1 tyrosine kinase activity and phosphorylation of SMAD1/5/8 at low concentrations of BMP9. The overall effect of the synergy between blood flow and BMP signaling is the inhibition of cell proliferation and the recruitment of mural cells, promoting vessel stabilization and quiescence. SMADs are likely the key mediators of these effects; however, this relationship is not yet firmly established.
Mentions: In contrast, Baeyens et al. (2016) demonstrate that blood flow sensitizes endothelial cells toward BMP9, changing its EC50 from 60 pg/ml in no-flow conditions to 3.5 pg/ml when exposed to 1.2 Pa of shear stress. Interestingly, ALK1 and ENG appear to have different roles during BMP9 flow signaling. Whereas ALK1 is required for any BMP9 signaling, ENG seems to be particularly critical for flow-dependent sensitization to low BMP9 concentrations. This finding fits well with the inducible mouse models of HHT and may explain why Alk1 deletion has a stronger impact in AVM formation than deletion of Eng. Mechanistically, Baeyens et al. (2016) propose that blood flow enables a physical interaction between ALK1 and ENG, which is responsible for the increased sensitivity to BMP9. Indeed, the authors were able to coimmunoprecipitate ALK1 and ENG when endothelial cells are exposed to flow but not in the presence of BMP9 alone. Collectively, the results by Baeyens et al. (2016) argue that enhanced BMP signaling is the key mediator for endothelial quiescence in response to flow (Fig. 1). Knockdown of either ALK1 or ENG reversed two known but critical effects of shear stress on endothelial cells: suppression of proliferation and mural cell recruitment (Baeyens et al., 2016). Intriguingly, in mice where ALK1 was randomly deleted in a subpopulation of labeled endothelial cells, only the ALK1-deficient cells proliferated more and showed decreased mural cell coverage. Given that endothelial cell proliferation and reduced recruitment of mural cells have previously been suggested to drive AVM formation, the newly identified convergence of blood flow and BMP signaling on these processes provides a molecular mechanism for the development of HHT lesions when ALK1 or ENG are defective.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Bone morphogenic proteins (BMPs) and blood flow regulate vascular remodeling and homeostasis. In this issue, Baeyens et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201603106) show that blood flow sensitizes endothelial cells to BMP9 signaling by triggering Alk1/ENG complexing to suppress cell proliferation and to recruit mural cells, thereby establishing endothelial quiescence.

No MeSH data available.


Related in: MedlinePlus