Published online before print July 24, 2006
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,1
* Department of Vascular Oncology and Metastasis, Joint Research Division Vascular Biology of the University of Heidelberg (Mannheim Campus) and the German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany; and
Department of Vascular Biology and Angiogenesis Research, Tumor Biology Center Freiburg, Germany
1 Correspondence: Department of Vascular Oncology and Metastasis, German Cancer Research Center, INF581, D-69120 Heidelberg, Germany. E-mail: augustin{at}angiogenese.de
ABSTRACT
Vascular receptor tyrosine kinases (RTK) have been identified as critical regulatory signaling molecules of developmental and adult vascular morphogenic processes [vascular endothelial growth factor (VEGF) receptors=sprouting; EphB receptors=assembly; Tie2 receptor=maturation and quiescence]. It is intriguing that the same molecules that control the growth of blood and lymphatic vessels play critical roles in the adult to regulate maintenance functions related to vascular homeostasis. VEGF is among the most potent inducers of vascular permeability. The second vascular RTK system, the interaction of paracrine-acting Angiopoietin-1 with its cognate receptor Tie2, acts as an endothelial maintenance and survival-mediating molecular system, which stabilizes the vessel wall and controls endothelial cell quiescence. The third vascular RTK system, the interaction of Eph receptors with their Eph family receptor-interacting protein (ephrin) ligands, transduces positional guidance cues on outgrowing vascular sprouts, which are critical for proper arteriovenous assembly and establishment of blood flow. As such, Eph-ephrin interactions act as an important regulator of cell–cell interactions, exerting propulsive and repulsive functions on neighboring cells and mediating adhesive functions. This review summarizes recent findings related to the roles of the Angiopoietin-Tie and the Eph-ephrin systems as regulators of cell trafficking in the vascular system. The recognition of vascular homeostatic functions of vascular RTKs marks an important change of paradigm in the field of angiogenesis research as it relates angiogenesis-inducing molecules to vascular maintenance functions in the adult. This may also broaden the scope of vascular RTK-targeted therapies.
Key Words: adhesion • angiogenesis • receptor tyrosine kinases • endothelium
INTRODUCTION
The vascular endothelium controls the passage of plasma and cells from the vascular to the extravascular space. As such, endothelial cells form a nonthrombogenic surface, which acts as permeability and extravasation barrier [1
]. Gowans [2
] and Palade and co-workers [3
] were first to independently report that leukocytes interact with the endothelium in postcapillary venules. These key observations suggested that the endothelial layer can undergo a transition from the quiescent, antiadhesive state to an activated, adhesive state [4
]. Further studies showed that activation of the endothelium is controlled by multiple factors and processes. These include physical damage, hypoxia, increased shear stress, as well as bacterial and viral infections. Collectively, these physical, chemical, and biological stimuli result in an inflammatory response, which is triggered by soluble factors such as thrombin, histamine, endotoxin, oxidized lipoproteins, prostaglandins, leukotrienes, IL-1, IL-6, IL-8, TNF-
, and vascular endothelial growth factor (VEGF). As a consequence, the endothelium becomes activated, which leads to the recruitment of inflammatory cells, thrombus formation, and local fluid accumulation, which is associated with locally reduced blood flow and increased permeability [1
, 4
].
The molecular mechanisms regulating the fast transition of the quiescent to the activated endothelium in response to tissue damage have only been partly uncovered. Activation of endothelial cells triggers immediate responses as well as a slower transcriptionally regulated response program. Immediate responses involve presynthesized molecules, which are stored within endothelial cells themselves. The cell-specific storage granules of endothelial cells are named after their discoverers Weibel-Palade bodies (WPB) [5 ]. The main constituent of WPB is the von Willebrand-factor (vWF). WPB store, in addition to the processed multimeric form of vWF, P-selectin, CD63, IL-8, endothelin-1, and its converting enzyme, tissue-type plaminogen activator (t-PA), and Angiopoietin-2 (Ang-2) [5 ]. All of these molecules are involved in the regulation of fast endothelial responses including hemostasis (vWF), inflammation (P-selectin, IL-8, Ang-2), hemodynamic adaptation (endothelin-1), fibrinolysis (t-PA), and permeability (Ang-2). WPB are released in response to multiple secretagogues (thrombin, histamine, peptide-leukotrienes, complement components C5a and C5b-9, superoxide anion, VEGF, sphingosine-1-phosphate, ceramides, purines, serotonin, epinephrine, and vasopressin) [5 ]. These mediators are potent inducers of inflammation, coagulation, angiogenesis, and other endothelial cell-response programs, suggesting that the release of WPB acts as the initiating step in the transition from the quiescent, resting endothelial phenotype to the activated, adhesive endothelium.
Endothelial cell activation is associated with a number of important local and systemic diseases such as atherosclerosis, thrombosis, tumor growth and metastasis, diabetes, retinopathies, and psoriatic skin alterations. It is intriguing that most of these disease processes are restricted to specific vascular beds; e.g., leukocyte adhesion and transmigration are primarily restricted to postcapillary venules. Likewise, platelets adhere primarily in arterial vessels, which are also predilection sites for atherosclerosis [1 ]. Correspondingly, vWF expression and storage in WPB are not uniform in all vessels. Similarly, site-specific metastatic tumor cell dissemination is (among other mechanisms) mediated by the preferential adhesion of metastasizing tumor cells to select organ endothelial cells [6 ]. These observations have stimulated research into the structural and functional analysis of vascular bed, specifically expressed endothelial cell surface molecules, which may serve as vascular bed-specific signaling molecules as well as organ specifically expressed adhesion molecules. For example, a number of endothelial cell specifically expressed cell surface molecules are expressed by angiogenic endothelial cells in the tumor-associated neovasculature. These "tumor endothelial markers" (TEMs) include TEM-1 (endosialin), TEM-5, TEM-7, and TEM-8 [7 8 9 ]. The molecular function of these molecules and their role as signaling or adhesive surface molecules are unknown and await a more detailed, functional analysis.
Inflammatory activation of the vascular endothelium is associated with the cell surface presentation of a number of different adhesion molecules. The respective "activation cocktail" defines the specific proadhesive phenotype of the activated endothelium. The repertoire of surface-expressed adhesion molecules allows the adhesion of selected circulating cell populations. The molecular cascade of events during leukocyte recruitment has been unraveled in great detail during the last two decades. Tethering of leukocytes and subsequent reversible rolling on the endothelium are mediated by the interaction with selectins. L-selectin is expressed by leukocytes and its ligand(s) by the activated endothelium. P-selectin is expressed by the endothelium and stored within WPB. Upon activation, P-selectin can be presented within seconds at the cell surface. Similarly, P-selectin is stored in platelet -granules and contributes to thrombus formation. E-selectin is expressed by cytokine-activated endothelial cells and mediates tethering and rolling of leukocytes to the activated endothelium. Following tethering and rolling, leukocytes are activated by chemokines, resulting in integrin activation on their cell surface. These integrins act as receptors for the cell-adhesion molecules ICAM-1, VCAM-1, and mucosal addressin cellular adhesion molecule-1 (MAdCAM-1), which are expressed by endothelial cells in response to inflammatory cytokines, e.g., TNF-, IL-1, and also by LPS. This interaction mediates the firm and irreversible adhesion of the leukocytes to the endothelium. Firm adhesion is followed by transendothelial migration and migration into the underlying tissue (for review, see refs. [4
, 10
]).
The interaction of platelets with the matrix of healthy and injured endothelium is primarily mediated by vWF, synthesized and released from endothelial cells and glycoprotein Ib (GPIb) expressed by platelets. In addition to vWF, the endothelium deposits in response to injury and inflammation other prothrombic constituents such as collagens, fibronectin, and tissue factor and creates an environment for thrombus formation. It is also well-appreciated that activated platelets release proinflammatory cytokines to modulate vascular inflammation, which may also contribute to the pathogenesis of atherosclerosis [11
, 12
]. Likewise, platelets have also been shown to stimulate endothelial WPB release, thereby linking thrombus formation and vascular inflammation mechanistically [13
].
It has become evident in recent years that angiogenesis-regulating vascular receptor tyrosine kinases (RTK) also play important roles in the regulation of endothelial cell activation during inflammation, thrombosis, and tumor metastasis. The emerging roles of the Angiopoietin-Tie system in controlling the quiescent resting state of the endothelium and of the ephrin system in cell-trafficking will be outlined in the following paragraphs.
CONTROL OF VASCULAR HOMEOSTASIS AND REMODELING THROUGH THE ANGIOPOIETIN-TIE SYSTEM
The Angiopoietin-Tie ligand-receptor system (Ang-Tie) was identified in 1996/1997 as the second vascular-specific RTK system (first: VEGF–VEGF receptor), which exerts rate-limiting signaling functions during angiogenesis and vascular remodeling [14 , 15 ]. It consists of two RTK, Tie1 and Tie2, and four corresponding Angiopoietin ligands: Ang-1, Ang-2, Ang-3, and Ang-4 [16 ]. Ang-1 and Ang-2 are the best-characterized ligands, which bind with similar affinity to the same binding site in the extracellular domain of the Tie2 receptor [17 ]. Binding of Ang-1 to Tie2 mediates rapid receptor autophosphorylation, promoting endothelial cell survival and migration, essentially by activation of the protein kinase B/Akt pathway [18 ]. In contrast, Ang-2 does not induce rapid Tie2 autophosphorylation, although it binds with similar affinity to the same site of Tie2, suggesting different regulatory mechanisms of Ang-1 and Ang-2 [16 ].
Ang-1-Tie2 signaling controls the quiescent endothelial cell phenotype
The physiological functions of the Angiopoietins in vivo have largely been deduced from the phenotypes of genetically manipulated loss-of-function and gain-of-function mice. Ang-1- and Tie2-deficient mice have largely complementary, embryonic lethal phenotypes [14
, 19
]. Tie2-deficient mice die approximately at E10.5 as a consequence of severe defects in vascular remodeling, poor vascular integrity, and perturbed vascular maturation [14
]. Ang-1-deficient mice have essentially a similar phenotype but die somewhat later during development at E12.5, which might be a result of compensatory mechanisms mediated by other angiopoietins [19
]. This suggests that Ang-1 is the bona fide agonistic ligand of Tie2, which regulates endothelial cell survival and blood vessel maturation. Constitutive low-level Tie-2 phosphorylation in the adult appears to be required to maintain the mature quiescent phenotype of the resting endothelium (Fig. 1
) [20
]. These quiescence-mediating functions correspond to the observation that Ang-1 exerts a vessel-sealing effect, acts anti-inflammatory, and protects against cardiac allograft arteriosclerosis, sepsis, and radiation-induced endothelial cell damage [21
22
23
24
25
]. Likewise, Ang-1 is a potent inhibitor of VEGF-induced ICAM-1 and VCAM-1 expression in vitro and inflammation-induced permeability in vivo [26
]. Moreover, Ang-1 prevents VEGF- and TNF--induced tissue factor expression [27
]. Taken together, low-level constitutive paracrine Ang-1 acts as a gatekeeper of vascular quiescence, maintaining the resting, antithrombotic, and antiadhesive state of the vascular endothelium.
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Figure 1. Regulation of vascular quiescence and responsiveness through the Ang-Tie system. The quiescent, resting endothelium (upper) has an antithrombotic and antiadhesive luminal cell surface. Low-level, paracrine-acting Ang-1 [multimeric (white)] induces constitutive Tie2 phosphorylation, which contributes to maintaining the vascular endothelium in the quiescent, resting state. Ang-2 [dimeric (gray)] is stored (with organ and caliber-specific variations) in endothelial cell WPB of the quiescent vasculature. One of the first steps in the cascade of events leading to endothelial cell activation (lower) is the release of the endothelial cell WPBs, which release liberates [among others (see text)], stored Ang-2, shifting the Ang-1/Ang-2 ratio locally in favor of Ang-2, where its release results in endothelial destabilization, yielding the endothelial cell layer responsive to the activities of other cytokines, e.g., proinflammatory stimuli. As such, Ang-2 acts as a built-in, autocrine switch of vascular quiescence and responsiveness.
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Regulation of inflammatory cell trafficking through the Ang-Tie system
Expression profiling studies has identified endothelial cells as the primary source of Ang-2 and a dramatic transcriptional regulation of Ang-2 production upon activation by, e.g., VEGF, fibroblast growth factor-2, and hypoxia [28
, 33
34
35
36
37
]. Correspondingly, the Ang-2 promoter contains positive and negative regulatory elements, which control endothelial, cell-specific Ang-2 expression [38
]. Recently, Ang-2 has been identified as a stored molecule of endothelial cell WPBs in cultured blood and lymphatic endothelial cells (ref. [39
] and U. Fiedler, unpublished data). Correspondingly, granular storage of Ang-2 in WPB can also be detected in vivo in the quiescent vasculature of human tissues with distinct organ-specific and caliber-specific variations. Stored Ang-2 is strongly detectable in the organs of the female reproductive system and in the brain. In contrast, endothelial cells in muscle are largely devoid of stored Ang-2 [40
], which can be secreted rapidly from endothelial cells by stimulation with multiple secretagogues releasing WPBs [38
]. Storage in endothelial cells, rapid release, and rapid Ang-2-mediated endothelial cell destabilization suggest that Ang-2 may be an autocrine-acting, negative regulator of endothelial cell quiescence. This concept is supported by recent inflammation experiments in Ang-2-deficient mice [40
]. Ang-2 null mice cannot elicit a rapid inflammatory response upon abdominal thioglycollate injection or Staphylococcus aureus infection. A detailed analysis of inflammatory leukocyte recruitment revealed that firm leukocyte adhesion, but not leukocyte rolling, is impaired in Ang-2-deficient mice. This suggests that surface presentation of P-selectin from WPBs is not perturbed in these mice. Yet, surface expression of adhesion molecules mediating firm adhesion appears to be impaired. In fact, Ang-2 could be shown to promote adhesion molecule expression by sensitizing endothelial cells toward cytokine-induced adhesion molecule expression [40
]. Thus, Ang-2 acts as a primer of inflammatory responses and as a critical regulator of vascular homeostasis and responsiveness toward cytokines. The detailed mechanisms by which Ang-2 is priming the endothelium toward cytokine responsiveness await further analysis. These experiments will also unravel the mechanisms through which Ang-2 regulates permeability (endothelial cell–cell contacts) and endothelial cell destabilization (endothelial cell–matrix contacts).
Taken together, the Ang-Tie system is critically involved in the regulation of the quiescent, antithrombotic, and antiadhesive state of the vascular endothelium, and Ang-1 acts anti-inflammatory by inhibiting adhesion molecule expression and permeability, and Ang-2 acts as a primer of fast, inflammatory responses by interfering with Ang-1-Tie2 signaling. Thus, Ang-2 is the dynamic, autocrine regulator of the quiescent state of the endothelium as a result of its storage in WPBs, its rapid release, and its strong transcriptional regulation (Fig. 1) .
Eph RECEPTORS AND EPHRIN LIGANDS AS REGULATORS OF CELL TRAFFICKING
Eph receptors and their corresponding ephrin ligands have been identified as the third vascular RTK system. These molecules have originally been characterized as neuronal guidance molecules [41 42 43 ]. Yet, genetic studies have revealed that B class Eph receptors and B class ephrin ligands exert rate-limiting functions during vascular morphogenic processes [41 42 43 ]. They do so by transducing guidance signals on outgrowing capillary sprouts, which facilitate network formation and proper establishment of an arteriovenous, asymmetrically organized microvasculature. Guidance signals are translated on the cellular level into successive migratory and adhesive events, but the Eph receptors and ephrin ligands are not just expressed by neuronal and vascular wall cells. Instead, the Eph-ephrin system appears to be a rather versatile cell migration and adhesion-controlling molecular system, which is operative in numerous cell populations. This review article focuses on the role of Eph receptors and ephrin ligands in controlling the trafficking of circulating cells. Yet, it is worth mentioning that Eph-ephrin interactions also transmit guidance signals on as diverse cell populations, such as gastrointestinal epithelial cells [44 ], cartilage and bone cells [45 ], and mammary epithelial cells [46 ].
Structure of Eph receptors and ephrin ligands
Eph receptors were first identified in the late 1980s [47
]. Today, they form the largest subgroup of RTK consisting of 10 A class receptors and six B class receptors [41
42
43
]. Eph receptors bind their ligands, the ephrins, which are correspondingly classified as A class (six members) and B class (three members). EphrinA ligands are GPI-anchored, peripheral membrane molecules. EphrinB ligands are transmembrane molecules with a short cytoplasmic tail, which itself transduces signals into B class ephrin-expressing cells. B class receptors and B class ligands have multiple, potential phosphorylation sites in their cytoplasmic tail. Likewise, receptors and ligands have a PDZ-binding site at their cytoplasmic C-terminal end. Eph receptor, and ephrin ligand interactions display a significant degree of receptor-ligand promiscuity. Yet, binding is mostly restricted to interactions within the same class of molecules; i.e., A class ephrins bind to A class Eph receptors, whereas B class ephrins bind to B class receptors. So far, only two exceptions to this rule have been described: EphrinA5 can interact with EphB2 and ephrinB ligands can interact with EphA4 [48
49
50
].
Given that Eph receptors and ephrin ligands are membrane molecules, interactions of receptors and ligands are dependent on the juxtapositional contact of neighboring cells. Signaling occurs following ligand-mediated receptor dimerization. Yet, receptors and ligands are also capable of clustering to form higher-order receptor-ligand complexes [51 , 52 ]. The degree of receptor clustering is dependent on the density of surface receptor expression [53 ]. Eph-ephrin signaling occurs classically in trans between two neighboring cells. Yet, it has also been reported more recently that cis signaling can lead to receptor activation on the same receptor and ligand-expressing cell [54 ].
Signaling through Eph receptors and ephrin ligands
Eph receptors are phosphorylated upon ephrin binding by transphosphorylation, acting as classical RTK, but they can also be phosphorylated by Src-family kinases [55
, 56
], which with respective phosphatases, promote signaling through the cytoplasmic tail of ephrinB ligands [57
]. The downstream signaling of Eph receptors and ephrin ligands occurs predominately through molecules that contain Src homology 2 domains [58
, 59
]. In addition, there are PDZ domain-containing proteins and Rho family guanine nucleotide-exchange factors, which mediate diverse downstream signaling events [60
]. The ubiquitin ligase Cbl is important for protein degradation after internalization [61
, 62
] and is also involved in the regulation of EphA receptor expression [63
]. EphrinA ligands have been demonstrated to be cleaved by a Kuzbanian metalloprotease (ADAM10) [63
, 64
]. Similarly, cleavage of ephrinB molecules has also been proposed [65
]. Functionally, forward Eph receptor signaling and reverse ephrin signaling transduce positional guidance cues on cells. These may be attractive or repulsive. On the cellular level, guidance cues are translated into migratory and adhesive events [42
, 59
, 66
, 67
].
Regulation of circulating cell trafficking by Eph receptors and ephrin ligands
Eph receptors and ephrin ligands have originally been described as neuron-specific molecules, which mediate attractive and repulsive guidance signals on outgrowing neurons [42
, 59
, 66
, 67
]. It is surprising that genetic experiments identified B class Eph receptors and B class ephrin ligands as rate-limiting regulators of vascular morphogenesis. The phenotype of EphB4-deficient and ephrinB-deficient mice is characterized by early embryonic lethality with an inability to properly position arteries and veins toward each other. As such, mice with targeted mutations of EphB4 or ephrinB2 are not capable of properly assembling the growing vascular network and establishing directional, arteriovenous blood flow [68
69
70
71
]. EphB4 is preferentially expressed by venous endothelial cells, whereas ephrinB2 is almost exclusively expressed by arterial and angiogenic endothelial cells [72
, 73
]. These studies have also shown that smooth muscle cells and pericytes express EphB receptor and ephrinB ligands. Correspondingly, the requirement of smooth muscle cell-expressed ephrinB2 for normal vessel development has recently been demonstrated through conditional gene-inactivation experiments [74
].
The arteriovenous, asymmetric expression of EphB4 and ephrinB2 has stimulated research into the identification of arteriovenously expressed molecules and the molecular and genetic mechanisms of arteriovenous differentiation. Genetic experiments in zebrafish suggest that arterial and venous fate determination occurs early during development, probably even prior to the formation of arteries and veins [75 ]. This may suggest that arterial and venous endothelial cell differentiation is an intrinsic property of the cells. Indeed, cultured arterial and venous endothelial cells appear to maintain some of their intrinsic, arteriovenous properties [76 ]. Yet, arterial ephrinB2 expression does not appear to be an intrinsic property of arterial endothelial cells. Instead, arteriovenous asymmetric ephrinB2 expression is rapidly lost upon transfer in culture of arterial and venous endothelial cells. This observed arteriovenous dedifferentiation has stimulated research into the mechanisms and microenvironmental milieu factors, which control arterial ephrinB2 expression. These studies have identified stimulation by VEGF, contact with smooth muscle cells, and fluid shear stress as regulators of endothelial cell ephrinB2 expression [77 78 79 80 ].
The ubiquitous expression of Eph receptors and ephrin ligands {among others: neuronal cells, endothelial cells, smooth muscle cells, pericytes, epithelial cells, tumor cells, circulating hematopoietic cells [T cell, platelets, dendritic cells (DC), monocytes/macrophages, B cells]} suggests much broader roles of Eph-ephrin signaling in transducing positional guidance cues among multiple contacting cell populations. A significant number of publications have been presented in recent years supporting the concept that Eph-ephrin interactions control the trafficking of circulating cells (Table 1 ). They do so by acting as adhesion molecules themselves as well as by modulating the activity of other adhesion molecules.
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Table 1. Regulation of Circulating Cell Functions by Eph Receptor and Ephrin Ligand Interactions
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The Eph-ephrin system also has a major role in the activation of platelets [106 ]. It has been reported that platelets express EphA4, EphB1, and ephrinB1 and that these molecules support the aggregation of platelets [104 ]. This process appears to be dependent on Eph receptor forward signaling, as ephrinB1 reverse signaling is not involved in platelet activation [103 ]. Similarly, EphA4 or ephrinB1 promotes integrin-mediated adhesion of platelets to fibrinogen [102 ].
Expression and functional effects of EphA family members have been detected in Langerhans-like dendritic cells (DC) [99 ]. EphA receptors are important for DC trafficking by regulating the adhesion to fibronectin [100 ]. EphB1 is expressed by plasmacytoid DC (PDC) and monocyte-derived DC (MDDC) [101 ]. B lymphocytes secrete ephrinA4, and it has been proposed to interact with DC in human tonsils [97 ]. The regulation of EphA7 during B lymphopoiesis points to a functional role of EphA7 in B cell differentiation [98 ]. Lastly, EphB4 expressing hematopoietic progenitors have been shown to differentiate to erythrocytes in the presence of erythropoietin and ephrinB2, suggesting an important role of ephrinB2 during erythropoiesis [107 ].
PERSPECTIVE
Vascular RTK have been identified as morphogenic signaling systems, which control the growth, assembly, and maturation of the vascular network during developmental and adult angiogenesis. The recognition that the same morphogenic molecules exert homeostatic maintenance functions in the adult marks an important change of paradigm. Future work will shed further light into the complexity of adult vascular RTK functions and likely unravel further surprises, which may expand the therapeutic range of vascular RTK-modulating drugs beyond angiogenesis-related applications.
Received November 13, 2005; revised June 22, 2006; accepted June 26, 2006.
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