1. High mitogenic stimulation arrests angiogenesis.
- Author
-
Pontes-Quero S, Fernández-Chacón M, Luo W, Lunella FF, Casquero-Garcia V, Garcia-Gonzalez I, Hermoso A, Rocha SF, Bansal M, and Benedito R
- Subjects
- Animals, Cell Proliferation drug effects, Cyclin-Dependent Kinase Inhibitor p21 genetics, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Endothelium, Vascular pathology, Human Umbilical Vein Endothelial Cells, Humans, Mice, Mice, Knockout, Neovascularization, Pathologic pathology, Receptors, Notch antagonists & inhibitors, Receptors, Notch metabolism, Retina, Retinal Vessels, Signal Transduction genetics, Vascular Endothelial Growth Factor A antagonists & inhibitors, Vascular Endothelial Growth Factor A metabolism, Endothelium, Vascular drug effects, Mitogens pharmacology, Neovascularization, Pathologic drug therapy, Signal Transduction drug effects
- Abstract
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.
- Published
- 2019
- Full Text
- View/download PDF