Role of Angiopoietin-2 in Vascular Physiology and Pathophysiology (original) (raw)
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Angiopoietins in angiogenesis and beyond
Expert Opinion on Investigational Drugs, 2003
The angiopoietin (Ang) family of growth factors includes four members, all of which bind to the endothelial receptor tyrosine kinase Tie2. Two of the Angs, Ang-1 and Ang-4 activate the Tie2 receptor, whereas Ang-2 and Ang-3 inhibit Ang-1-induced Tie2 phosphorylation. While genetic models have underscored the importance of Angs in the developing cardiovascular system, other studies have demonstrated that Ang-1 promotes endothelial cell survival, sprouting and tube formation. More recently, a new aspect of the biology of this class of growth factors has emerged, namely the ability of Ang-1 to reduce inflammation. This review presents an outline of Angs and their receptors, examining their structure, expression, signalling, regulation and biological significance and comments on the role and potential usefulness of Angs in medicine.
Angiopoietin-2, a Natural Antagonist for Tie2 That Disrupts In Vivo Angiogenesis
Science, 1997
normal vascular development has been verified by examination of mice with inacti-~ntagonist f o r~i e 2 That vating mutations in the genes for these factors or their receptors, which can exhibit defects in the earliest stages of endothelial Disrupts i viva An 9 i og esis cell generation (5). Negative angiogenic regulators such as oroliferin-related ~r o t e i n (4, angiostatin (7), and endostaiin
Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling
Journal of Clinical Investigation, 2012
Angiopoietin-2 (ANG-2) is a key regulator of angiogenesis that exerts context-dependent effects on ECs. ANG-2 binds the endothelial-specific receptor tyrosine kinase 2 (TIE2) and acts as a negative regulator of ANG-1/TIE2 signaling during angiogenesis, thereby controlling the responsiveness of ECs to exogenous cytokines. Recent data from tumors indicate that under certain conditions ANG-2 can also promote angiogenesis. However, the molecular mechanisms of dual ANG-2 functions are poorly understood. Here, we identify a model for the opposing roles of ANG-2 in angiogenesis. We found that angiogenesis-activated endothelium harbored a subpopulation of TIE2-negative ECs (TIE2 lo). TIE2 expression was downregulated in angiogenic ECs, which abundantly expressed several integrins. ANG-2 bound to these integrins in TIE2 lo ECs, subsequently inducing, in a TIE2-independent manner, phosphorylation of the integrin adaptor protein FAK, resulting in RAC1 activation, migration, and sprouting angiogenesis. Correspondingly, in vivo ANG-2 blockade interfered with integrin signaling and inhibited FAK phosphorylation and sprouting angiogenesis of TIE2 lo ECs. These data establish a contextual model whereby differential TIE2 and integrin expression, binding, and activation control the role of ANG-2 in angiogenesis. The results of this study have immediate translational implications for the therapeutic exploitation of angiopoietin signaling.
Biological characterization of angiopoietin‐3 and angiopoietin‐4
The FASEB Journal, 2004
The angiopoietin (Ang) family of growth factors includes Ang1, Ang2, Ang3, and Ang4, all of which bind to the endothelial receptor tyrosine kinase Tie2. Ang3 (mouse) and Ang4 (human) are interspecies orthologs. In experiments with human endothelial cell lines, Ang3 was identified as an antagonist of Tie2 and Ang4 was identified as an agonist of Tie2. However, the biological roles of Ang3 and Ang4 are unknown. We examined the biological effect of recombinant Ang3 and Ang4 proteins in primary cultured endothelial cells and in vivo in mice. Recombinant Ang3 and Ang4 formed disulfide-linked dimers. Ang4 (400 ng/mL) markedly increased Tie2 and Akt phosphorylation in primary cultured HUVECs whereas Ang3 (400 ng/mL) did not produce significant changes. Accordingly, Ang4, but not Ang3, induced survival and migration in primary cultured HUVECs. Unexpectedly, intravenously administered Ang3 (30 g) was more potent than Ang4 (30 g) in phosphorylating the Tie2 receptor in lung tissue from mice in vivo. Accordingly, Ang3 was more potent than Ang4 in phosphorylating Akt in primary cultured mouse lung microvascular endothelial cells. Ang3 and Ang4 both produced potent corneal angiogenesis extending from the limbus across the mouse cornea in vivo. Thus, Ang3 and Ang4 are agonists of Tie2, but mouse Ang3 has strong activity only on endothelial cells of its own species.-Lee, H.
Journal of Cell Science, 2006
The receptor tyrosine kinase Tie2 is highly expressed in endothelial cells and is crucial for angiogenesis and vascular maintenance. The ligands for Tie2 are the angiopoietins, of which angiopoietin-1 and angiopoietin-2 have been the most studied. Angiopoietin-1 has been characterized as the primary activating ligand for Tie2 whereas the role of angiopoietin-2 remains controversial; activating Tie2 in some studies and inhibiting Tie2 in others. Our studies were aimed at understanding the regulation of Tie2 in endothelial cells by angiopoietin-1 and angiopoietin-2 and revealed that both ligands activated Tie2 in a concentration-dependent manner. Angiopoietin-2 was considerably weaker at activating Tie2 compared with angiopoietin-1 suggesting that angiopoietin-2 may be a partial agonist. Activation of Tie2 by these ligands resulted in differential turnover of the receptor where binding of angiopoietin-1, and to a lesser extent angiopoietin-2, induced rapid internalization and degradat...
Journal of Biological Chemistry, 1998
Angiopoietin-1 and its putative natural antagonist, angiopoietin-2, were recently isolated, and the critical role of angiopoietin-1 in embryogenic angiogenesis was demonstrated by targeted gene disruption. Specific biological effects of angiopoietin-1, however, have yet to be defined. In this study we demonstrate that angiopoietin-1, but not angiopoietin-2, is chemotactic for endothelial cells. In contrast, angiopoietin-1 as well as angiopoietin-2 exhibit no proliferative effect on endothelial cells. Excess soluble Tie2, but not Tie1 receptor, abolish the chemotactic response of endothelial cells toward angiopoietin-1. Angiopoietin-2 dose-dependently blocks directed migration toward angiopoietin-1, consistent with the role of angiopoietin-2 as a naturally occurring inhibitor of angiopoietin-1. Fibroblasts stably transfected with Tie2 receptor exhibit chemotactic responses for both angiopoietin-1 and angiopoietin-2. Fibroblasts stably expressing a transfected chimeric receptor consisting of the ectodomain of TrkC fused to the cytoplasmic domain of Tie2 also exhibit a chemotactic response to neurotrophin 3 (NT-3), a specific ligand for TrkC. Endothelial cells are shown to express angiopoietin-2 mRNA and protein, indicating the potential for autocrine activation of angiopoietin/Tie2. Finally, the demonstration that Tie2 as well as angiopoietin-1 are expressed in normal human arteries and veins suggests that the role of angiopoietin/Tie2 may extend beyond embryonic angiogenesis to maintaining integrity of the adult vasculature.
Angiopoietin-Tie signalling in the cardiovascular and lymphatic systems
Clinical science (London, England : 1979), 2017
Endothelial cells that form the inner layer of blood and lymphatic vessels are important regulators of vascular functions and centrally involved in the pathogenesis of vascular diseases. In addition to the vascular endothelial growth factor (VEGF) receptor pathway, the angiopoietin (Ang)-Tie system is a second endothelial cell specific ligand-receptor signalling system necessary for embryonic cardiovascular and lymphatic development. The Ang-Tie system also regulates postnatal angiogenesis, vessel remodelling, vascular permeability and inflammation to maintain vascular homoeostasis in adult physiology. This system is implicated in numerous diseases where the vasculature has an important contribution, such as cancer, sepsis, diabetes, atherosclerosis and ocular diseases. Furthermore, mutations in the TIE2 signalling pathway cause defects in vascular morphogenesis, resulting in venous malformations and primary congenital glaucoma. Here, we review recent advances in the understanding o...
Clinical Hemorheology and Microcirculation, 2011
Angiopoietins are important growth factors for vascular development and quiescence. They are promising targets for 12 pro-or anti-angiogenic therapies in diverse pathologies, but the mechanisms of the ANGPT/TIE2 system are complex and not 13 well understood. In the present study, the separate and combined effects of angiopoietin 1 and angiopoietin 2 were studied, using 14 a recently developed in vitro angiogenesis model that allows both a quantitative and qualitative evaluation of the angiogenic 15 cascade. This cell culture model was performed with microvascular endothelial cells (ECs) originating from different vascular 16 beds, i.e. dermal ECs and cardiac ECs. In addition, the expression of the angiopoietins and the receptors, TIE1 and TIE2 was 17 analyzed with RT-qPCR. This study revealed that the angiopoietins provoked a differential response in the two endothelial 18 cultures. Both angiopoietin 1 as well as angiopoietin 2 elicited an angiogenic cascade in the dermal ECs but not in the cardiac 19 ECs. In addition, the RT-qPCR data revealed marked differences in the endogenous expression pattern of these factors, indicating 20 that the origin of endothelial cells might have an important impact on their angiogenic potential. 21 U n c o r r e c t e d A u t h o r P r o o f 2 W. De Spiegelaere et al. / In vitro angiogenesis, angiopoietins highly complex, and a better knowledge of the molecular mechanisms of angiogenesis will aid the 30 development of future therapies that aim to enhance or inhibit angiogenesis [9]. 31 A range of growth factors has already been described to influence the process of angiogenesis. Amongst 32 these, the family of vascular endothelial growth factors (VEGFs) is the best known and best studied 33 factors. VEGFs induce capillary sprouting by stimulating endothelial migration and proliferation. Due to 34 their importance both in development and in various pathological situations, VEGF has been extensively 35 studied in the past decades [24]. The angiopoietins are another family of endothelial specific growth 36 factors, but their role during angiogenesis is still elusive. They are expressed in a range of developing 37 and adult tissues [11, 12, 17]. It is currently hypothesized that the angiopoietins play a major role during 38 maturation of the vasculature following VEGF induced angiogenesis [2, 26]. Angiopoietin 1 (ANGPT1) 39 and angiopoietin 2 (ANGPT2) are the most common and best described members of the angiopoietin 40 family. These ligands both bind the endothelial specific TIE2 (TEK) receptor [28]. ANGPT1 is described 41 as a vascular maturation factor; it induces lumen formation and vascular quiescence by activating the 42 TIE2 receptor. ANGPT2 is an antagonist of ANGPT1, as it binds the TIE2 receptor with similar affinity 43 as ANGPT1, but has a weak ability to activate TIE2 [7, 23]. In this way, ANGPT2 induces vascular 44 destabilization, which can either lead to the onset of angiogenesis or endothelial regression, depending 45