Review ArticleTie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling
Introduction
Tie1 and Tie2 constitute a distinct family of receptor tyrosine kinases found to be expressed mainly in endothelial cells [1], [2]. The Tie receptors have many interesting cellular effects and potential therapeutic applications, which make them molecules of significant interest to vascular biologists.
Angiopoietins 1–4 (Ang1–Ang4) constitute a family of growth factors known to function as ligands for the Tie2 receptor [3], [4], [5]. The characteristic features of angiopoietins are opposing effects on Tie2 receptor activation and signaling outcome [3], [4], [5]. Ang1 has been shown to act as an obligatory agonist promoting structural integrity of blood vessels [3], [6], whereas Ang2 has been found to function as a naturally occurring antagonist promoting either vessel growth or regression depending on the levels of other growth factors, such as VEGF-A [4], [7]. However, in certain in vitro models, Ang1 and Ang2 have similar responses, and in vivo studies, including studies of Ang2-deficient mice [8], also suggest that Ang2 can have an agonistic role depending on the tissue environments and the experimental conditions [9], [10], [11], [12], [13]. The effects of Ang3 and Ang4 have been less characterized, but they also show context-dependent actions as antagonistic and agonistic ligands, respectively [5], [14]. The mechanisms underlying the different effects of angiopoietins on Tie2 activation are not yet known.
The formation of a functional vasculature is a complex process requiring spatial and temporal coordination of multiple angiogenic factors, receptors, intracellular signaling pathways and regulatory factors. One emerging theme is that VEGFs and angiopoietins play complementary roles. In many contexts, Ang1 and VEGF-A have been shown to have synergistic effects [15], [16], [17], [18], [19], [20], but Ang1 can also counteract the permeability [15], [21] and proangiogenic effects of VEGF-A [22], [23], [24], and VEGF-A can change the proangiogenic outcome of Ang2 signaling through Tie2 [7], [22], [25], [26]. Thus, the net effect of Tie signaling is dependent not only on angiopoietins, but also on other growth factors and likely also on other, as yet unidentified regulatory factors.
Signaling through Tie2 has been extensively studied, and the results suggest that signaling involving phosphatidylinositol 3′ kinase (PI3-K) activation is a major pathway [18], [27], [28], [29], [30], [31], [32]. However, the lack of an identified ligand has made it difficult to characterize the function of Tie1. Intriguingly, recent studies suggest a novel ligand-independent function for Tie1. This involves shedding of the receptor [33], [34], [35], [36], [37], [38] and heteromeric complex formation with Tie2 [36], [37], [39], [40]. Additionally, although previous studies failed to demonstrate binding of angiopoietins to Tie1 [3], [4], [5], it has recently been found that Ang1 and Ang4 can in fact activate Tie1 [40].
Mutations in Tie2 are found in vascular anomalies, including venous malformations [41], [42] and intramuscular hemangiomas [43]. Changes in the expression of Tie2 and angiopoietins are found in a wide range of diseases including psoriasis [44], pulmonary hypertension [45], [46], infantile hemangiomas [47] and different tumors [48]. However, the exact mechanisms by which Tie signaling may contribute to the diseases are not yet known.
Section snippets
Structural characteristics of angiopoietins
Angiopoietins contain an amino-terminal angiopoietin-specific domain followed by a coiled-coil domain, a linker peptide and a carboxy-terminal fibrinogen homology domain [3], [4], [5]. The fibrinogen homology domain is responsible for receptor binding, the coiled-coil domain is required for dimerization of angiopoietin monomers, and the short amino-terminal region forms ring-like structures that cluster dimers into variable sized multimers necessary for Tie2 activation [49], [50], [51]. One
Tie2/Ang1 signaling
Genetic studies using targeted mutations in mice have been used to study the function of Tie signaling. A common feature of mouse models lacking Tie1 [56], Tie2 [56], [57], Ang1 [6] or Ang2 [8] is that vasculogenesis, the formation of blood vessels by in situ differentiation of endothelial cell precursors, proceeds normally, but remodeling and maturation of the vessels are defective. Tie2−/− mice die between embryonic day 9.5 and 12.5 due to lack of remodeling of the primary capillary plexus.
Angiopoietin-2 functions as a context-dependent antagonist or agonist
Ang2 was found to bind to Tie2 but failed to induce autophosphorylation in endothelial cells [4]. Transgenic overexpression of Ang2 led to a phenotype similar to that observed in Ang1- or Tie2-deficient mice leading to the hypothesis that Ang2 blocks the stimulatory effects of Ang1, thereby acting as a natural antagonist for Ang1 [4]. In contrast to the relatively stable expression of Ang1, expression of Ang2 was found predominantly at sites of vascular remodeling, including female reproductive
Angiopoietin-3 and angiopoietin-4
Ang3 and Ang4 were found by homology cloning by virtue of primary structure similarity to Ang1 and Ang2 and by their ability to bind to Tie2 [5]. Mouse Ang3 and human Ang4 represent interspecies orthologues, but they have relatively low (65%) amino acid identity [5]. Their functions are far less characterized than those of Ang1 and Ang2. Mouse Ang3 is expressed at low levels in many tissues [5], whereas Ang4 mRNAs are expressed at high levels in the lungs, with lower levels in other tissues [5]
Tie signaling in late development
Tie2 is constitutively expressed and phosphorylated at a low level in adult mice, suggesting that Tie2 activation is required in adult tissues to maintain the mature quiescent phenotype of the vasculature [103]. While studies of gene-deficient mice have demonstrated the importance of Tie signaling in early development, analysis of mosaic mouse models [104], [105] and different blocking experiments using soluble Tie2 receptors [12], [106], [107] and inhibitors against Tie2 [78] and Ang2 [96],
Functions of the Tie1 receptor
In spite of the structural homology between Tie2 and Tie1, none of the known angiopoietins was found to bind to Tie1 when native or engineered chimeric ligands were used [3], [4], [5]. Because of the lack of an identified ligand, the function of Tie1 has remained enigmatic, although in vivo studies indicate an essential role for Tie1 in vascular development [56], [112], [113]. Mice lacking Tie1 die between E13.5 and the immediate postnatal period due to severe hemorrhages and edema suggesting
Angiopoietins stimulate lymphangiogenesis
Tie2 expression in lymphatic endothelial cells [116], [117], [118] and the lymphatic phenotype in Ang2−/− mice and its rescue by Ang1 [8] suggest a role for Tie signaling in lymphatic vessels. The ability of Ang1 to promote lymphangiogenesis has been demonstrated by viral overexpression of Ang1 in mouse skin [117] and cornea [118]. Ang1-induced lymphangiogenic activity was found to be accompanied by upregulation of VEGFR-3 [117], which functions as a receptor for the lymphangiogenesis
Tie2 and Ang1 are important in the hematopoietic system
Endothelial and hematopoietic stem cells are derived from a common hemangioblast progenitor. Tie1 and Tie2 are expressed in certain hematopoietic cells, suggesting a potential role in establishment or maintenance of hematopoietic system [119], [120], [121], [122]. In fact, Tie2−/− mice show severely impaired hematopoiesis [121]. However, in chimeric mice with both normal and Tie receptor-deficient hematopoietic stem cells, it was found that Tie2 is not required for embryonic hematopoiesis [104]
Role of Tie signaling in the regulation of mesenchymal cells
A characteristic feature of Tie2−/− and Ang1−/− mice, patients with venous malformations due to mutations in Tie2 and lymphatic vessels in Ang2−/− mice is defective vessel remodeling and abnormal smooth muscle cell (SMC) layering around affected vessels. The lack of Tie2 expression in SMCs has led to a hypothesis that mesenchymal-derived Ang1 activates Tie2 in endothelial cells in the developing vessels, and the endothelial cells in turn produce and secrete soluble chemoattractants to recruit
Tie signaling in nerves and angiopoietin interactions with integrins
Interestingly, Tie2 expression is found in certain neuronal cells where it has neuroprotective effects and stimulates growth responses in vitro [131], [132], [133]. Additionally, overexpression of Ang1 in the forebrain of mice leads to increased vascularization and also to changes in dendrite organization of the neurons [134]. However, Tie2 was not found to be expressed in neurons or dendritic processes in vivo, and it is speculated that the effect of Ang1 on neurons might be mediated by an
Concluding remarks
Although it is evident that Tie signaling is essential for vascular remodeling and maturation, the detailed molecular mechanisms of how Tie signaling contribute to these processes are less clear. The wide range of activities suggested for Tie receptors and angiopoietins with apparently conflicting results make an attempt to generate a unifying model for their biological functions difficult. This may simply reflect the complexity and complex regulation of Tie signaling as well as a lack of
Acknowledgments
This work was supported by NIH grants AR36820 and AR048564 (B.R. Olsen) and EMBO Fellowship (L. Eklund). We would like to thank Eileen Boye for helpful comments on the manuscript and Yulia Pittel for excellent secretarial assistance.
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