Trends in Genetics
Volume 29, Issue 3, March 2013, Pages 140-149
Journal home page for Trends in Genetics

Review
Robustness in angiogenesis: Notch and BMP shaping waves

https://doi.org/10.1016/j.tig.2012.11.008Get rights and content

Vascular patterning involves sprouting of blood vessels, which is governed by orchestrated communication between cells in the surrounding tissue and endothelial cells (ECs) lining the blood vessels. Single ECs are selected for sprouting by hypoxia-induced stimuli and become the ‘tip’ or leader cell that guides new sprouts. The ‘stalk’ or trailing ECs proliferate for tube extension and lumenize the nascent vessel. Stalk and tip cells can dynamically switch their identities during this process in a Notch-dependent manner. Here, we review recent studies showing that bone morphogenetic protein (BMP) signaling coregulates Notch target genes in ECs. In particular, we focus on how Delta-like ligand 4 (DLL4)–Notch and BMP effector interplay may drive nonsynchronized oscillatory gene expression in ECs essential for setting sharp tip–stalk cell boundaries while sustaining a dynamic pool of nonsprouting ECs. Deeper knowledge about the coregulation of vessel plasticity in different vascular beds may result in refinement of anti-angiogenesis and vessel normalization therapies.

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

References (99)

  • A. Conidi

    Few Smad proteins and many Smad-interacting proteins yield multiple functions and action modes in TGFbeta/BMP signaling in vivo

    Cytokine Growth Factor Rev.

    (2011)
  • M.C. Ramel et al.

    Spatial regulation of BMP activity

    FEBS Lett.

    (2012)
  • J. Nickel

    Intricacies of BMP receptor assembly

    Cytokine Growth Factor Rev.

    (2009)
  • J. Cai

    BMP signaling in vascular diseases

    FEBS Lett.

    (2012)
  • R. Kopan et al.

    The canonical Notch signaling pathway: unfolding the activation mechanism

    Cell

    (2009)
  • J.W. Lowery et al.

    BMP signaling in vascular development and disease

    Cytokine Growth Factor Rev.

    (2010)
  • L. David

    Emerging role of bone morphogenetic proteins in angiogenesis

    Cytokine Growth Factor Rev.

    (2009)
  • N. Ricard

    BMP9 and BMP10 are critical for postnatal retinal vascular remodeling

    Blood

    (2012)
  • J.D. Kim

    Context-dependent proangiogenic function of bone morphogenetic protein signaling is mediated by disabled homolog 2

    Dev. Cell

    (2012)
  • M. Mahmoud

    Endoglin and activin receptor-like-kinase 1 are co-expressed in the distal vessels of the lung: implications for two familial vascular dysplasias, HHT and PAH

    Lab. Invest.

    (2009)
  • E. Pardali

    Signaling by members of the TGF-beta family in vascular morphogenesis and disease

    Trends Cell Biol.

    (2010)
  • B. Larrivee

    ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway

    Dev. Cell

    (2012)
  • F. Li

    Endothelial Smad4 maintains cerebrovascular integrity by activating N-cadherin through cooperation with Notch

    Dev. Cell

    (2011)
  • G. Bai

    Id sustains Hes1 expression to inhibit precocious neurogenesis by releasing negative autoregulation of Hes1

    Dev. Cell

    (2007)
  • A.M. Henderson

    The basic helix-loop-helix transcription factor HESR1 regulates endothelial cell tube formation

    J. Biol. Chem.

    (2001)
  • A. Fantin

    Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction

    Blood

    (2010)
  • H.H. Outtz

    Notch1 controls macrophage recruitment and Notch signaling is activated at sites of endothelial cell anastomosis during retinal angiogenesis in mice

    Blood

    (2011)
  • B. Mengel

    Modeling oscillatory control in NF-kappaB, p53 and Wnt signaling

    Curr. Opin. Genet. Dev.

    (2010)
  • O. Pourquie

    Vertebrate segmentation: from cyclic gene networks to scoliosis

    Cell

    (2011)
  • M. Bordonaro

    The Notch ligand Delta-like 1 integrates inputs from TGFbeta/Activin and Wnt pathways

    Exp. Cell Res.

    (2011)
  • Y. Fu

    Differential regulation of transforming growth factor beta signaling pathways by Notch in human endothelial cells

    J. Biol. Chem.

    (2009)
  • K. Niessen

    ALK1 signaling regulates early postnatal lymphatic vessel development

    Blood

    (2010)
  • K. Niessen

    The Notch1-Dll4 signaling pathway regulates mouse postnatal lymphatic development

    Blood

    (2011)
  • W. Zheng

    Notch restricts lymphatic vessel sprouting induced by vascular endothelial growth factor

    Blood

    (2011)
  • P.D. Upton

    Bone morphogenetic protein (BMP) and activin type II receptors balance BMP9 signals mediated by activin receptor-like kinase-1 in human pulmonary artery endothelial cells

    J. Biol. Chem.

    (2009)
  • K. Miyazono

    BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk

    Cytokine Growth Factor Rev.

    (2005)
  • C. Sieber

    Recent advances in BMP receptor signaling

    Cytokine Growth Factor Rev.

    (2009)
  • D.A. William

    Identification of oscillatory genes in somitogenesis from functional genomic analysis of a human mesenchymal stem cell model

    Dev. Biol.

    (2007)
  • M.E. Fortini

    Notch signaling: the core pathway and its posttranslational regulation

    Dev. Cell

    (2009)
  • T. Pierfelice

    Notch in the vertebrate nervous system: an old dog with new tricks

    Neuron

    (2011)
  • I. Geudens et al.

    Coordinating cell behaviour during blood vessel formation

    Development

    (2011)
  • T. Tammela

    VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling

    Nat. Cell Biol.

    (2011)
  • R. Benedito

    Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF–VEGFR2 signalling

    Nature

    (2012)
  • L. Jakobsson

    Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting

    Nat. Cell Biol.

    (2010)
  • R. Blanco et al.

    VEGF and Notch in tip and stalk cell selection

    Cold Spring Harb. Perspect. Med.

    (2012)
  • J.J. Tung

    Tips, stalks, tubes: Notch-mediated cell fate determination and mechanisms of tubulogenesis during angiogenesis

    Cold Spring Harb. Perspect. Med.

    (2012)
  • M.R. Urist

    Bone: formation by autoinduction

    Science

    (1965)
  • J.M. Wozney

    Novel regulators of bone formation: molecular clones and activities

    Science

    (1988)
  • D.O. Wagner

    BMPs: from bone to body morphogenetic proteins

    Sci. Signal.

    (2010)
  • Cited by (0)

    View full text