FOXO1 couples metabolic activity and growth state in the vascular endothelium

Wilhelm, Kerstin; Happel, Katharina; Eelen, Guy; Schoors, Sandra; Oellerich, Mark F.; Lim, Radiance; Zimmermann, Bárbara H.; Aspalter, Irene M.; Franco, Cláudio A.; Boettger, Thomas; Braun, Thomas; Fruttiger, Marcus; Rajewsky, Klaus; Keller, Charles; Brüning, Jens C.; Gerhardt, Holger; Carmeliet, Peter; Potente, Michael

doi:10.1038/nature16498

Cited by 491 publications

(535 citation statements)

References 42 publications

Supporting

Mentioning

488

Contrasting

Order By: Relevance

“…Our results show that increased EC number in adults was associated with increased diameter in capillaries, principally those near veins. Mice in which ECs lack Rbpjk (Rbpj) or Foxo1 also have increased EC number and an increase in retinal vessel diameter (Ehling et al, 2013;Wilhelm et al, 2016). Notably, however, both these mutants show an increase in vein diameter, which we did not observe.…”

Section: Discussioncontrasting

confidence: 46%

“…In the case of Rbpjk mutants, the difference is likely to be due to increased EC size as well as number (Ehling et al, 2013). Although EC size was not reported for the Foxo1 mutants, it is at least possible it is increased given their upregulation of MYC (Wilhelm et al, 2016), a known positive regulator of cell growth (Dang, 2013). The absence of increased artery or vein diameter in the Bak −/− Bax EC/EC mice despite increased cell number suggests there must be strong feedback mechanisms in place to maintain a preferred diameter in these vessels, regardless of cell number.…”

Section: Discussionmentioning

confidence: 93%

See 1 more Smart Citation

Apoptosis regulates endothelial cell number and capillary vessel diameter but not vessel regression during retinal angiogenesis

Koenig

Grant

et al. 2016

Development

View full text Add to dashboard Cite

The growth of hierarchical blood vessel networks occurs by angiogenesis. During this process, new vessel growth is accompanied by the removal of redundant vessel segments by selective vessel regression ('pruning') and a reduction in endothelial cell (EC) density in order to establish an efficient, hierarchical network. EC apoptosis has long been recognised for its association with angiogenesis, but its contribution to this process has remained unclear. We generated mice in which EC apoptosis was blocked by tissue-specific deletion of the apoptosis effector proteins BAK and BAX. Using the retina as a model, we found that apoptosis made a minor contribution to the efficiency of capillary regression around arteries where apoptosis was most concentrated, but was otherwise dispensable for vessel pruning. Instead, apoptosis was necessary for the removal of non-perfused vessel segments and the reduction in EC density that occurs during vessel maturation. In the absence of apoptosis, increased EC density resulted in an increase in the diameter of capillaries, but not arteries or veins. Our findings show that apoptosis does not influence the number of vessels generated during angiogenesis. Rather it removes non-perfused vessel segments and regulates EC number during vessel maturation, which has vessel-specific consequences for vessel diameter.

show abstract

Section: Discussioncontrasting

confidence: 46%

Section: Discussionmentioning

confidence: 93%

Apoptosis regulates endothelial cell number and capillary vessel diameter but not vessel regression during retinal angiogenesis

Koenig

Grant

et al. 2016

Development

View full text Add to dashboard Cite

show abstract

“…Each group contained five hearts. Measurement of coronary vessel density was performed as described previously (Wilhelm et al, 2016). Randomly chosen fields were used to quantify vascularization at the ventricle surface (40 dpf ).…”

Section: Quantitative Analysis Of Cardiomyocyte and Coronary Vessel Dmentioning

confidence: 99%

Vinculin b deficiency causes epicardial hyperplasia and coronary vessel disorganization in zebrafish

Cheng

Miao

et al. 2016

Development

View full text Add to dashboard Cite

Coronary vessel development is a highly coordinated process during heart formation. Abnormal development and dysfunction of the coronary network are contributory factors in the majority of heart disease. Understanding the molecular mechanisms that regulate coronary vessel formation is crucial for preventing and treating the disease. We report a zebrafish gene-trap vinculin b (vclb) mutant that displays abnormal coronary vessel development among multiple cardiac defects. The mutant shows overproliferation of epicardiumderived cells and disorganization of coronary vessels, and they eventually die off at juvenile stages. Mechanistically, Vclb deficiency results in the release of another cytoskeletal protein, paxillin, from the Vclb complex and the upregulation of ERK and FAK phosphorylation in epicardium and endocardium, causing disorganization of endothelial cells and pericytes during coronary vessel development. By contrast, cardiac muscle development is relatively normal, probably owing to redundancy with Vcla, a vinculin paralog that is expressed in the myocardium but not epicardium. Together, our results reveal a previously unappreciated function of vinculin in epicardium and endocardium and reinforce the notion that well-balanced FAK activity is essential for coronary vessel development.

show abstract

“…ANG1 is an agonistic paracrine ligand of Tie2 that stimulates Akt-dependent phosphorylation and nuclear exclusion of the Forkhead box protein O1 (FOXO1) transcription factor (10). FOXO1 inactivation downregulates the expression of genes involved in endothelial destabilization, apoptosis, metabolism, and growth control (11,12). In contrast, ANG2 is an endothelial autocrine ligand that functions as a context-dependent weak agonist or antagonist of Tie2.…”

Section: Introductionmentioning

confidence: 99%

Tie1 controls angiopoietin function in vascular remodeling and inflammation

Korhonen

Lampinen

Giri³

et al. 2016

Journal of Clinical Investigation

208

279

View full text Add to dashboard Cite

The angiopoietin/Tie (ANG/Tie) receptor system controls developmental and tumor angiogenesis, inflammatory vascular remodeling, and vessel leakage. ANG1 is a Tie2 agonist that promotes vascular stabilization in inflammation and sepsis, whereas ANG2 is a context-dependent Tie2 agonist or antagonist. A limited understanding of ANG signaling mechanisms and the orphan receptor Tie1 has hindered development of ANG/Tie-targeted therapeutics. Here, we determined that both ANG1 and ANG2 binding to Tie2 increases Tie1-Tie2 interactions in a β 1 integrin-dependent manner and that Tie1 regulates ANG-induced Tie2 trafficking in endothelial cells. Endothelial Tie1 was essential for the agonist activity of ANG1 and autocrine ANG2. Deletion of endothelial Tie1 in mice reduced Tie2 phosphorylation and downstream Akt activation, increased FOXO1 nuclear localization and transcriptional activation, and prevented ANG1-and ANG2-induced capillary-to-venous remodeling. However, in acute endotoxemia, the Tie1 ectodomain that is responsible for interaction with Tie2 was rapidly cleaved, ANG1 agonist activity was decreased, and autocrine ANG2 agonist activity was lost, which led to suppression of Tie2 signaling. Tie1 cleavage also occurred in patients with hantavirus infection. These results support a model in which Tie1 directly interacts with Tie2 to promote ANG-induced vascular responses under noninflammatory conditions, whereas in inflammation, Tie1 cleavage contributes to loss of ANG2 agonist activity and vascular stability. The Journal of Clinical Investigation R E S E A R C H A R T I C L E3 4 9 6 jci.org Volume 126 Number 9 September 2016We found that angiopoietins promoted a direct interaction of Tie1 and Tie2 and that this interaction was regulated by integrin β 1 . ANG1-and ANG2-induced Tie2 activation and vascular remodeling were reduced or absent in mice where Tie1 was deleted in vascular endothelial cells. Tie1 deletion also attenuated ANG1-induced Akt activation and nuclear exclusion of FOXO1. We found that Tie1 was suppressed via ectodomain cleavage during acute inflammation and that this was associated with reduced agonistic activity of ANG2 and decreased Tie2 signaling. These results indicate that the agonist action of ANG2 is attenuated in inflammation and that Tie1 is an essential component of the angiopoietin signaling system that has potential for therapeutic targeting in disease. ResultsAngiopoietins induce direct interaction of Tie1 and Tie2. To investigate the dynamics of the Tie receptors in angiopoietin signaling, we transfected HUVECs with retroviral vectors expressing full-length (FL) Tie1 and Tie2, tagged on the C terminus with mCherry and GFP, respectively. Stimulation of FL-Tie2-GFP and FL-Tie1-mCherry expressing endothelial cells with COMP-Ang1 (CAng1) (49) or with recombinant human ANG2 induced colocalization of Tie1 and Tie2 in endothelial cell-cell junctions ( Figure 1A and Supplemental Video 1; supplemental material available online with this article; doi:10.1172/JCI84923DS1) (44,45,50). To investigat...

show abstract

FOXO1 couples metabolic activity and growth state in the vascular endothelium

Cited by 491 publications

References 42 publications

Apoptosis regulates endothelial cell number and capillary vessel diameter but not vessel regression during retinal angiogenesis

Apoptosis regulates endothelial cell number and capillary vessel diameter but not vessel regression during retinal angiogenesis

Vinculin b deficiency causes epicardial hyperplasia and coronary vessel disorganization in zebrafish

Tie1 controls angiopoietin function in vascular remodeling and inflammation

Contact Info

Product

Resources

About