Trends in Genetics
ReviewRobustness in angiogenesis: Notch and BMP shaping waves
Highlights
► BMP and DLL4-Notch signaling crosstalk drives oscillatory gene expression in endothelium. ► Nonsynchronized oscillation networks of BMP-SMAD and Notch effectors dynamically affect EC competences. ► The HES/HEY molecular oscillators critically depend on ID-mediated BMP-SMAD signaling in ECs. ► Tip-stalk cell competence and nonsprouting are all balanced by nonsynchronized oscillators.
Section snippets
Development of a branched vascular tree
The proper formation of blood vessels is critical for developmental growth as well as for tissue growth and physiology beyond birth. The blood vessel circulatory system comprises arteries, capillaries, and veins, and it fuels nearly every tissue with oxygen and nutrients, clears tissues of metabolic waste, and transports liquids and cells. Failure to establish a hierarchical branched vessel network leads to embryonic lethality, whereas deregulation of vessel patterning after birth contributes
An introduction to BMP signaling
BMPs are secreted ligands of the transforming growth factor β (TGF-β) family, which also includes TGF-β, BMPs, growth, and differentiation factors (GDFs), activins, and nodal. The BMPs can be subdivided based on their structural properties and documented ligand–receptor interactions into four groups: (i) the BMP2 and -4 subgroup; (ii) the growth and differentiation factor (GDF)5, -6, and, -7 group; (iii) the BMP5, -6, -7, and -8 group; and (iv) the BMP9 and -10 group (reviewed in [10]). BMPs
DLL–Notch and BMPs in vascular development
Activation of Notch by cell-bound ligands, such as DLL4 in ECs, results in proteolytic cleavage of the Notch intracellular domain (NICD) and its translocation to the nucleus, where it is recruited to target genes via interaction with the DNA-binding protein CSL/RBPJ/CBF1 [34]; Box 1; Figure 1). This complex recruits additional transcriptional activators and induces target genes, such as those encoding hairy and enhancer of split (HES) and hairy/enhancer-of-split-related with YRPW motif (HEY),
BMP–SMADS and IDs as essential components of the HES1 molecular oscillator
The mutual interdependence between Notch and BMP–SMAD cascades in ECs may result in dynamic amplification and subsequent inhibition of downstream targets of either cascade 51, 67 (Figure 2a). It was proposed that the resulting nonsynchronized oscillations of BMP–SMAD and Notch effectors provide individual ECs stalk and tip cell competence. In the absence of pro-angiogenic stimuli, ECs become periodically competent to each phase [20] (Figure 3a). The intervals between each competence phase
Concluding remarks
Dynamic nonsynchronized oscillatory networks of BMP–SMAD and Notch intracellular effector proteins may establish rapid and robust tip–stalk cell selection. This model is compatible with tip and stalk cells being in continuous flux, the shuffling of tip and stalk cell position, and Notch-mediated macrophage-assisted anastomosis 68, 69. Notably, this cross-signaling also leads to maintenance of a dynamic pool of permissive, nonsprouting ECs. Similar to the cells in the roof plate and floor plate
Acknowledgments
We thank past and present team members for stimulating discussions and support. We apologize to authors whose relevant work was not cited because of space restrictions. This work was supported by VIB, OT-09/053, and GOA-11/012 from the KU Leuven Research Council.
Glossary
- Angiogenesis
- the formation of new blood vessels from pre-existing vessels by vessel sprouting (sprouting angiogenesis) or splitting (intussusception).
- Endothelial cells (ECs)
- cells that line the interior surface of blood and lymphatic vessels.
- Lateral inhibition
- an event in which a cell adopts a particular phenotype and prevents its immediate neighbor from acquiring the same phenotype through Notch-mediated signaling.
- Morphogen
- a signaling factor that elicits different cellular responses in responding
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