Control of vascular morphogenesis and homeostasis through the angiopoietin–Tie system

Key Points

  • The assembly of a functional vascular system requires coordinated signalling between various growth factors and receptors. The Tie receptors and their angiopoietin (Ang) ligands have important functions during embryonic vessel assembly and maturation and control adult vascular homeostasis.

  • ANG1 and TIE2-deficiency in mice lead to lethality at embryonic day 10.5 (E10.5) as a consequence of perturbed vessel organization and maturation. TIE1-deficient mice have no overt angiogenesis-related phenotype but die in late gestation as a consequence of widespread oedema and haemorrhage. ANG2 is dispensable for embryonic development, but mice that overexpress ANG2 have essentially the same phenotypes as ANG1- and TIE2-deficient mice.

  • Constitutive stimulation of TIE2 by ANG1 leads to vessel maturation and contributes to the maintenance of vascular quiescence. Vascular quiescence is associated with the recruitment of peri-endothelial cells (pericytes and smooth muscle cells).

  • TIE2 activation drives several signalling pathways. The dominant signalling pathway is the phosphoinositide 3-kinase (PI3K)–AKT pathway, which transduces survival signals.

  • The antagonist of constitutive ANG1–TIE2 signalling, ANG2, is produced and stored by endothelial cells (ECs). It acts through an autocrine-loop mechanism to control EC responsiveness to multiple cytokines, which include angiogenesis-inducing cytokines, such as vascular endothelial growth factor (VEGF), permeability-inducing molecules, such as histamine and bradykinin, and inflammation-inducing factors, such as tumour-necrosis factor-α (TNFα).

  • TIE1 is an orphan receptor of which the mechanism of action has not been uncovered. An emerging concept suggests that TIE1–TIE2 heterodimerization might contribute to TIE2 signal transduction.

  • Non-vascular functions of Ang–Tie signalling are only recently being uncovered. Most notably, ANG1–TIE2 signalling has a crucial role in maintaining the haematopoietic stem cell niche.

Abstract

Angiogenesis, the growth of blood vessels, is a fundamental biological process that controls embryonic development and is also involved in numerous life-threatening human diseases. Much work in the field of angiogenesis research has centred on the vascular endothelial growth factor (VEGF)–VEGF receptor system. The Tie receptors and their angiopoietin (Ang) ligands have been identified as the second vascular tissue-specific receptor Tyr kinase system. Ang–Tie signalling is essential during embryonic vessel assembly and maturation, and functions as a key regulator of adult vascular homeostasis. The structural characteristics and the spatio-temporal regulation of the expression of receptors and ligands provide unique insights into the functions of this vascular signalling system.

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Figure 1: Physiological vascular effects of the Angiopoietin–Tie system.
Figure 2: Angiopoietin–Tie effects during pathological vascular adaptation.
Figure 3: Structural properties of the Tie receptors and the Angiopoietin ligands.
Figure 4: Angiopoietin–Tie signalling in maintaining endothelial cell quiescence.
Figure 5: Angiopotein–Tie signalling during endothelial cell activation.

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Acknowledgements

The authors thank several colleagues and their students for assistance in collecting material for this review. We would like to particularly acknowledge A. Benest, M. Thomas and S. Bartels. The authors gratefully acknowledge M.O. Steinmetz (Paul Scherrer Institut, Villinge, Switzerland) for the rotary shadowing electron microscopic images shown in figure 3. We apologize to all those, whose work could not be cited owing to space limitations. Work in the authors' laboratories is supported by grants from the Deutsche Forschungsgemeinschaft, Finish Cancer Organizations, the Academy of Finland, Helsinki University Central Hospital, the Korea Science and Engineering Foundation (KOSEF), the Louis Jeantet Foundation, the Novo Nordisk Foundation, the Aventis Foundation, the German–Israel Foundation and the European Union and the National Institutes of Health.

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Correspondence to Hellmut G. Augustin.

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H.G. Augustin, G.Y. Koh and K. Alitalo declare no competing financial interests. G. Thurston is an employee of Regeneron Pharmaceuticals.

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Glossary

Endothelial cell

A cell type that forms a single layer in the inner lining of blood and lymphatic vessels. Conceptually, the vascular endothelium can be considered to be a systemically disseminated organ system.

Angioblast

A precursor cell of endothelial cells that originates from a common lineage with haematopoietic precursor cells, or haemangioblasts.

Angiogenic cascade

The sequential series of events that lead to the formation of new blood vessels: proteolysis, migration, proliferation, lumen formation and capillary network organization.

Vessel quiescence

The non-proliferating, anti-thrombotic, anti-inflammatory and non-angiogenic default status of resting endothelial cells and the surrounding peri-endothelial cells.

Pericyte

A mesenchymal-like peri-endothelial cell in capillaries that controls the resting phenotype of adjacent endothelial cells. Pericyte markers are NG2 proteoglycan, desmin, platelet-derived growth factor-β (PDGFRβ), α-smooth muscle actin and RGS5.

Chylous ascites

The presence of a milky fluid that contains suspended fat in the peritoneal cavity. Also called chyloperitoneum.

Hyaloid vessel

One of several vessels that run through the vitreous humour of the eye during the fetal stage of development. These supply the fetal lens and regress during late embryonic and early postnatal development.

Corpus luteum

Latin for yellow body, this temporary endocrine structure in the female ovary produces progesterone, which is required to maintain pregnancy.

Inflammation

The biological response programme of vascular tissues to harmful stimuli and irritants. The hallmarks of inflammation are pain, heat, redness, swelling and tissue damage.

Vessel co-option

Describes the utilization of a pre-existing vasculature by a growing tumour.

Hypoxia

A deficiency in oxygen. Hypoxia is a powerful regulator of vascular functions. Oxygen gradients have morphogenic properties during angiogenesis and vascular remodelling.

Biomarker

A substance that is used as an indicator of a biological state. Frequently analysed biomarkers in the circulation include growth factors, soluble adhesion molecules and soluble receptors. Also called a surrogate marker.

Pericyte dropout

The loss of peri-endothelial pericyte coverage. This is a hallmark of vascular-destabilizing diseases, such as diabetic retinopathy.

Soluble receptor

A receptor that has the extracellular domain of a membrane receptor that can bind to the ligand and prevent it from binding to the cell surface receptor. As such, soluble receptors act as decoys and inhibit signal transduction.

Coiled-coil domain

A structural protein motif with multiple α-helices that coil together like the strands of a rope.

Rotary shadowing

An electron microscopic technique that is based on the rapid freezing of a specimen, followed by the vacuuming off of ice crystals and rotary spraying with metal vapour. This yields a contrast in the electron micrograph after removal of the organic material.

Shear stress

The biomechanical force that acts on the vessel wall as a consequence of the tangential force exerted by the flowing blood. This stabilizes the endothelial layer and prevents cell death.

Weibel–Palade body

Named after its discoverers, this body is a storage granule of endothelial cells that contains von Willebrand Factor and a few other molecules, including P-selectin and angiopoietin 2.

Von Willebrand Factor

A blood glycoprotein that is involved in haemostasis.

Adherens junction

A junctional cell–cell contact that is composed of homotypic adhesion molecules of the cadherin family that associate with catenins.

Tight junction

A junctional cell–cell contact that forms an essentially impermeable barrier. This is composed of molecules of the occludin and claudin families.

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Augustin, H., Young Koh, G., Thurston, G. et al. Control of vascular morphogenesis and homeostasis through the angiopoietin–Tie system. Nat Rev Mol Cell Biol 10, 165–177 (2009). https://doi.org/10.1038/nrm2639

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