Tip Cells in Angiogenesis

Marchien G Dallinga, Academic Medical Center, Amsterdam, The Netherlands
Sonja EM Boas, Centrum Wiskunde & Informatica, Amsterdam, The Netherlands
Ingeborg Klaassen, Academic Medical Center, Amsterdam, The Netherlands
Roeland HM Merks, Centrum Wiskunde & Informatica, Amsterdam, The Netherlands
Cornelis JF van Noorden, Academic Medical Center, Amsterdam, The Netherlands
Reinier O Schlingemann, Academic Medical Center, Amsterdam, The Netherlands

Published online: May 2015

DOI: 10.1002/9780470015902.a0025977

Abstract

In angiogenesis, the process in which blood vessel sprouts grow out from a pre‐existing vascular network, the so‐called endothelial tip cells play an essential role. Tip cells are the leading cells of the sprouts; they guide following endothelial cells and sense their environment for guidance cues. Because of this essential role, the tip cells are a potential therapeutic target for anti‐angiogenic therapies, which need to be developed for diseases such as cancer and major eye diseases. The potential of anti‐tip cell therapies is now widely recognised, and the surge in research this has caused has led to improved insights in the function and regulation of tip cells, as well as the development of novel in vitro and in silico models. These new models in particular will help understand essential mechanisms in tip cell biology and may eventually lead to new or improved therapies to prevent blindness or cancer spread.

Key Concepts

  • Sprouting angiogenesis is led by tip cells, which can sense their environment and direct the sprouting process.
  • Tip cells are followed by stalk cells, which have a more proliferative phenotype.
  • The number of tip cells is regulated by lateral inhibition between the tip cells and the stalk cells; the tip cells prevent the adjacent cells from becoming tip cells and thereby optimise the number of tip cells.
  • The tip cell and stalk cell phenotype are definite, and stalk cells can overtake tip cells through stochastic cellular and environmental differences, the stalk cells then become tip cells and force the former tip cells to become stalk cells.
  • Tip cells exist in human umbilical vein endothelial cell cultures and can therefore be studied in vitro.

Keywords: angiogenesis; tip cell; stalk cell; anti‐angiogenic therapy; VEGF

Figure 1. (a) Tip cells in the retina of a mouse (white arrow) at the top of newly formed capillaries during angiogenesis at 5 days after birth (P5). The capillaries are stained with Isolectin B4 (green). (b) Higher magnification of the edge of an area in the mouse retina where tip cells at the top of newly formed capillaries are shown to have filopodia (arrow heads). Bars are 250 µm.
Figure 2. Overview of the key regulatory pathways for tip cell selection. Tip cells are represented in red, stalk cells in blue and the phalanx cells in orange. (a) VEGF: VEGF‐A is produced upon hypoxia; tip cells express VEGFR2 and ‐3, two receptors that exert the pro‐angiogenic effects of VEGF. Soluble VEGFR1 is produced by stalk cells and acts as a sink for VEGF to prevent signalling in stalk cells. (b) Neuropilins: NRP‐1 acts as a co‐receptor for VEGFR2 to enhance VEGF signalling. (c) Notch1‐Dll4: Dll4 is expressed by tip cells, Notch1 by stalk cells. Upon binding, Notch1 is cleaved, and the intracellular domain (NICD) is translocated to the nucleus where it recruits transcription factors to replace expression of tip cell genes by expression of stalk cell genes. (d) Angiopoietins and Tie2: Ang1 is expressed in mature vessels and its main function is vessel stabilisation. (e) Ang2 can bind Tie2 to inhibit Ang1‐mediated phosphorylation of Tie2; it also binds integrins on tip cells to enhance sprouting. (f) BMPs and SMADs: Pro‐ and anti‐angiogenic BMPs bind to their receptor and phosphorylate SMAD1/5/8. In tip cells, the SMAD1/5/8 complex induces polarisation and migration. (g) In stalk cells, the SMAD1/5/8 complex forms a complex with NICD to promote the stalk cell phenotype.
Figure 3. In vivo, in vitro and in silico models for angiogenesis. (a) Fli1a‐eGFP transgenic zebrafish, at 24‐h post fertilisation. At this stage, sprouting occurs in the intersegmental vessels (white arrows) and tip cells are present on each sprouting vessel. (b) CD34+ cell in a human umbilical vein endothelial cell (HUVEC) culture. HUVECs were grown on coverslips coated with gelatin and stained for F‐actin (red), CD34 (green) and DAPI (blue). (c) In silico vascular network formed from a spheroid of endothelial cells by a mechanism of cell–cell contact‐inhibited chemotaxis (Merks et al., ). Tip cells are indicated in red.
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References

Ashton N (1966) Oxygen and the growth and development of retinal vessels. In vivo and in vitro studies. American Journal of Ophthalmology 62: 412–435.

Aster JC (2014) In brief: Notch signalling in health and disease. The Journal of Pathology 232 (1): 1–3 Available at: http://www.ncbi.nlm.nih.gov/pubmed/24122372 (accessed October 26, 2014).

Augustin HG, Koh GY, Thurston G, et al. (2009) Control of vascular morphogenesis and homeostasis through the angiopoietin‐Tie system. Nature Reviews. Molecular Cell Biology 10 (3): 165–177.

Ausprunk DH and Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Medicine 1 (1): 27–31.

Ausprunk DH and Folkman J (1977) Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. Microvascular Research 14: 53–65.

Beets K, Huylebroeck D, Moya IM, et al. (2013) Robustness in angiogenesis: Notch and BMP shaping waves. Trends in Genetics 29 (3): 140–149.

Benedito R, Rocha SF, Woeste M, et al. (2012) Notch‐dependent VEGFR3 upregulation allows angiogenesis without VEGF‐VEGFR2 signalling. Nature 484 (7392): 110–114.

Bentley K, Franco CA, Philippides A, et al. (2014) The role of differential VE‐cadherin dynamics in cell rearrangement during angiogenesis. Nature Cell Biology 16 (4): 309–321.

Bentley K, Mariggi G, Gerhardt H, et al. (2009) Tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis. PLoS Computational Biology 5 (10): e1000549.

Bentley K, Gerhardt H and Bates PA (2008) Agent‐based simulation of notch‐mediated tip cell selection in angiogenic sprout initialisation. Journal of Theoretical Biology 250 (1): 25–36.

Carmeliet P, Ferreira V, Breier G, et al. (1996) Abnormal vessel development and lethality in embryos lacking a single VEGF allele. Nature 380: 435–439.

Clark ER, Hitschler WJ, Kirby‐Smith HT, et al. (1931) General observations on the ingrowth of new blood vessels into standardized chambers in the rabbit's ear, and the subsequent changes in the newly grown vessels over a period of months. The Anatomical Record 50 (2): 129–167.

Cohen M, Georgiou M, Stevenson NL, et al. (2010) Dynamic filopodia transmit intermittent Delta‐Notch signaling to drive pattern refinement during lateral inhibition. Developmental Cell 19 (1): 78–89.

Collier J, Monk NAM, Maini PK, et al. (1996) Pattern formation by lateral inhibition with feedback: a mathematical model of delta – Notch intercellular signalling. Journal of Theoretical Biology 183: 429–446.

David L, Feige J‐J and Bailly S (2009) Emerging role of bone morphogenetic proteins in angiogenesis. Cytokine & Growth Factor Reviews 20 (3): 203–212.

Djordjevic S and Driscoll PC (2013) Targeting VEGF signalling via the neuropilin co‐receptor. Drug Discovery Today 18 (9–10): 447–455.

Dooley K and Zon LI (2000) Zebrafish: a model system for the study of human disease. Current Opinion in Genetics & Development 10 (3): 252–256.

Eelen G, Cruys B, Welti J, et al. (2013) Control of vessel sprouting by genetic and metabolic determinants. Trends in Endocrinology and Metabolism 24 (12): 589–596.

Felcht M, Luck R, Schering A et al. (2012) Angiopoietin‐2 differentially regulates angiogenesis through TIE2 and integrin signaling. The Journal of Clinical Investigation 122 (6): 1991–2005.

Ferrara N, Carver‐Moore K, Chen H, et al. (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380: 439–442.

Folkman J (1974) Tumor angiogenesis factor tumor angiogenesis factor1. Cancer Research 34: 2109–2113.

Folkman J (1971) Tumor angiogenesis, therapeutic implications. The New England Journal of Medicine 285 (21): 1182–1186.

Fruttiger M (2002) Development of the mouse retinal vasculature: angiogenesis versus vasculogenesis. Investigative Ophthalmology & Visual Science 43 (2): 522–527.

Gerhardt H, Golding M, Fruttiger M, et al. (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. The Journal of Cell Biology 161 (6): 1163–1177.

Graner F and Glazier JA (1992) Simulation of biological cell sorting using a two‐dimensional extended potts model. Physical Review Letters 69 (13): 2013–2016.

Hellström M, Phng LK, Hofmann JJ, et al. (2007) Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445 (7129): 776–780.

Jakobsson L, Franco CA, Bentley K, et al. (2010) Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting. Nature Cell Biology 12 (10): 943–953.

Koch S and Claesson‐Welsh L (2012) Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harbor Perspectives in Medicine 2 (7): a006502.

Loeb J (1893) Ueber die entwicklung vom Fischembryonen ohne Kreislauf. Archiv für die gesamte Physiologie des Menschen und der Tiere 54: S.525–S.531.

Merks RMH, Perryn ED, Shirinifard A, et al. (2008) Contact‐inhibited chemotaxis in de novo and sprouting blood‐vessel growth. PLoS Computational Biology 4 (9): e1000163.

Michaelson IC (1948) Vascular morphogenesis in the retina of the cat. Journal of Anatomy 82 (3): 1948.

Moya IM, Umans L, Maas E, et al. (2012) Stalk cell phenotype depends on integration of Notch and Smad1/5 signaling cascades. Developmental Cell 22 (3): 501–514.

Van Noorden CJF, Meade‐tollin LC and Bosman FT (1998) Metastasis. The spread of cancer cells to distant sites implies a complex series of cellular abnormalities caused, in part, by genetic aberrations. American Scientist 86 (2): 130–141.

Palm MM, Dallinga MG, van Dijk E, et al. (2014) Computational screening of angiogenesis model variants predicts that differential chemotaxis helps tip cells move to the sprout tip and accelerates sprouting. arXiv:1409.5895 [q‐bio.CB].

Phng L‐K and Gerhardt H (2009) Angiogenesis: a team effort coordinated by notch. Developmental Cell 16 (2): 196–208.

Phng L‐K, Stanchi F and Gerhardt H (2013) Filopodia are dispensable for endothelial tip cell guidance. Development (Cambridge, England) 140 (19): 4031–4040.

Roux W (1895) Gesammelte abhandlung der entwicklungsmechanik der Organismus. Leipzig: Engelmann.

Sabin FR (1917) Preliminary note on the differentiation of angioblasts and the method by which they produce blood‐vessels, blood plasma and red blood‐cells as seen in the living chick. The Anatomical Record 13: 199–204.

Schlingemann RO, Rietveld FJR, De Waal RMW, et al. (1990) Leukocyte antigen CD34 is expressed by a subset of cultured endothelial cells and on endothelial abluminal microprocesses in the tumor stroma. Laboratory Investigation 62 (6): 690–696.

Siemerink MJ, Klaassen I, Vogels IMC, et al. (2012) CD34 marks angiogenic tip cells in human vascular endothelial cell cultures. Angiogenesis 15 (1): 151–163.

Smith LEH, Wesoloiuski E, Mclellan A, et al. (1994) Oxygen‐induced retinopathy in the mouse. Investigative Ophthalmology & Visual Science 35 (1): 101–111.

Soker S, Takashima, Miao HQ, et al. (1998) Neuropilin‐1 Is expressed by endothelial and tumor cells as an isoform‐specific receptor for vascular endothelial growth factor. Cell 92: 735–745.

Sperry RW (1963) Chemoaffinity in the orderly growth of nerve fiber patterns and connections. Proceedings of the National Academy of Sciences of the United States of America 50 (4): 703–710.

Sprinzak D, Lakhanpal A, Lebon L, et al. (2010) Cis‐interactions between Notch and Delta generate mutually exclusive signalling states. Nature 465: 86–90.

Sprinzak D, Lakhanpal A, Lebon L et al. (2011) Mutual inactivation of Notch receptors and ligands facilitates developmental patterning. PLoS Computational Biology 7 (6): e1002069.

Valdembri D, Caswell PT, Anderson KI, et al. (2009) Neuropilin‐1/GIPC1 signaling regulates alpha5beta1 integrin traffic and function in endothelial cells. PLoS Biology 7 (1): e25.

Wiley DM and Jin S‐W (2011) Bone Morphogenetic Protein functions as a context‐dependent angiogenic cue in vertebrates. Seminars in Cell & Developmental Biology 22 (9): 1012–1018.

Witmer AN, Dai J, Weich HA, et al. (2002) Expression of vascular endothelial growth factor receptors 1, 2, and 3 in quiescent endothelia. The Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society 50 (6): 767–777.

Zelzer E and Shilo B (2000) Cell fate choices in Drosophila tracheal morphogenesis. BioEssays 22: 219–226.

Further Reading

Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Medicine 1 (1): 27–31.

Potente M, Gerhardt H and Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146 (6): 873–887.

Siemerink MJ, Klaassen I, Van Noorden CJF and Schlingemann RO (2013) Endothelial tip cells in ocular angiogenesis: potential target for anti‐angiogenesis therapy. Journal of Histochemistry and Cytochemistry 61 (2): 101–115.

Related Sub-Topics:

Cell Signalling | Cell Biology of Organogenesis | Cell Biology of Cancer | Techniques in Cell Biology | Intracellular and Extracellular Signalling | Cell Motility | Biochemistry of Cell Motility
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Article Title: Tip Cells in Angiogenesis
 
How to Cite close
Dallinga, Marchien G, Boas, Sonja EM, Klaassen, Ingeborg, Merks, Roeland HM, van Noorden, Cornelis JF, and Schlingemann, Reinier O(May 2015) Tip Cells in Angiogenesis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025977]