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.
Highlights
Growing or hypoxic tissues secrete vascular endothelial growth factor (VEGF)
Some groups reported no significant differences in the number of Erg+ cells (ECs) in s-phase (BrdU+) in retinas of Dll[4] heterozygous mice or after treatment with a general y-secretase inhibitor (DAPT)[11,20], whereas others have seen an increase in the frequency of BrdU+ or Ki67 + ECs in retina vessels of mice treated with different Notch signalling inhibitors (y-secretase inhibitor or Dll4-Fc proteins)[5,22,23]
Live imaging of intersegmental arteries development showed an increase in the number of ECs in zebrafish embryos with a morpholino-induced reduction of Dll[4] and Rbpj expression[4]
Summary
Growing or hypoxic tissues secrete vascular endothelial growth factor (VEGF). Activation of VEGFR2, the most important VEGF receptor, triggers a series of phosphorylation cascades, including ERK (MAPK) activation, that are considered essential for EC motility and proliferation. According to this model, tip cells should proliferate more than stalk cells because they have higher-VEGF signalling and lower-Notch signalling. This approach reveals that ECs have a bell-shaped dose–response to mitogenic stimuli in vivo that is highly dependent on the vascular developmental context This is due to a cell-cycle checkpoint molecular mechanism that is elicited when VEGF stimulation is high or Notch signalling is low during angiogenesis. In these conditions, ECs have high-ERK activity, which induces the expression of the cell-cycle inhibitor p21, and the ensuing cellcycle arrest enhances endothelial sprouting and migration, but blocks angiogenesis due to the inhibition of endothelial proliferation. Our study revisits the important role of Notch and VEGF in the balance of endothelial proliferation and sprouting during angiogenesis, and provides significantly more molecular, cellular and temporal resolution on the underlying mechanism
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
