High mitogenic stimulation arrests angiogenesis.
Animals
Cell Proliferation
/ drug effects
Cyclin-Dependent Kinase Inhibitor p21
/ genetics
Endothelium, Vascular
/ drug effects
Human Umbilical Vein Endothelial Cells
Humans
Mice
Mice, Knockout
Mitogens
/ pharmacology
Neovascularization, Pathologic
/ drug therapy
Receptors, Notch
/ antagonists & inhibitors
Retina
Retinal Vessels
Signal Transduction
/ drug effects
Vascular Endothelial Growth Factor A
/ antagonists & inhibitors
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
01 05 2019
01 05 2019
Historique:
received:
11
12
2018
accepted:
03
04
2019
entrez:
3
5
2019
pubmed:
3
5
2019
medline:
7
6
2019
Statut:
epublish
Résumé
Appropriate therapeutic modulation of endothelial proliferation and sprouting is essential for the effective inhibition of angiogenesis in cancer or its induction in cardiovascular disease. The current view is that an increase in growth factor concentration, and the resulting mitogenic activity, increases both endothelial proliferation and sprouting. Here, we modulate mitogenic stimuli in different vascular contexts by interfering with the function of the VEGF and Notch signalling pathways at high spatiotemporal resolution in vivo. Contrary to the prevailing view, our results indicate that high mitogenic stimulation induced by VEGF, or Notch inhibition, arrests the proliferation of angiogenic vessels. This is due to the existence of a bell-shaped dose-response to VEGF and MAPK activity that is counteracted by Notch and p21, determining whether endothelial cells sprout, proliferate, or become quiescent. The identified mechanism should be considered to achieve optimal therapeutic modulation of angiogenesis.
Identifiants
pubmed: 31043605
doi: 10.1038/s41467-019-09875-7
pii: 10.1038/s41467-019-09875-7
pmc: PMC6494832
doi:
Substances chimiques
Cdkn1a protein, mouse
0
Cyclin-Dependent Kinase Inhibitor p21
0
Mitogens
0
Receptors, Notch
0
VEGFA protein, human
0
Vascular Endothelial Growth Factor A
0
vascular endothelial growth factor A, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2016Commentaires et corrections
Type : ErratumIn
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