Skip to Main contentScienceDirectJournals BooksRegisterSign in Sign inRegisterJournals BooksHelpAngiopoietin 2Ang2 is upregulated in tumor blood vessels in a wide range of human cancers and appears to have a mainly agonistic effect on Tie2 signaling, although the mechanisms have yet to be elucidated.From: Pathobiology of Human Disease, 2014Related terms:CapillaryProteinNeoplasmVon Willebrand FactorAngiopoietinAngiopoietin 1VasculotropinRetinalHypoxiaView all TopicsDownload as PDFSet alertAbout this pageHandbook of Immunohistochemistry and in situ Hybridization of Human Carcinomas, Volume 4Kohkichi Hata, in Handbook of Immunohistochemistry and in Situ Hybridization of Human Carcinomas, 2006Sample CollectionTo investigate the expression of Ang1, Ang2, and Tie2 genes, we collected ovarian tissues from 33 patients during operation. The 14 patients having normal ovaries with CL ranged in age from 21 to 50 years (median 43 years), and all subjects had regular menstrual cycles. The final diagnoses were myoma uteri (n = 9), cervical cancer stage Ib (n = 2), serous cystadenoma (n = 2), and hemorrhagic corpus luteum (n = 1). The 19 patients with ovarian cancer were aged from 19 to 76 years (median 56 years), and 8 of them were premenopausal. Their tumors were classified as serous cystadenocarcinoma (stage Ia) (n = 1), mucinous cystadenocarcinoma (stage Ia) (n = 1), endometrioid carcinoma (stage Ia) (n = 1), clear cell carcinoma (stage Ia) (n = 1), mucinous cystadenocarcinoma (stage Ic) (n = 3), endometrioid carcinoma (stage II) (n = 1), serous cystadenocarcinoma (stage III) (n = 7), endometrioid carcinoma (stage III) (n = 1), undifferentiated carcinoma (stage III) (n = 1), and serous cystadenocarcinoma (stage IV) (n = 2).These women were electively admitted to our gynecology ward. Asymptomatic women with a positive result from an ovarian cancer screening program were excluded. If the ovaries were removed for diagnostic or therapeutic purposes, then a portion of the tissue was taken for the subsequent analysis of specific gene expression. The remainder of each tissue was used for routine histologic investigation. All research was conducted with informed consent.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/S1874578405801138The Origin and Regulation of the Renal VasculatureMaria Luisa S. Sequeira Lopez, in Kidney Development, Disease, Repair and Regeneration, 2016AngiopoietinsAngiopoietins are a family of growth factors that includes the glycoproteins angiopoietin 1 and 2 and the orthologs 3 (in the mouse) and 4 (in human). The receptors are tyrosine kinases and include Tie1 and Tie2. Angiopoietin 1 is produced by smooth muscle cells and pericytes, and acts on Tie2 receptors expressed by endothelial cells. Angiopoietin 2, produced by endothelial cells, also binds to the Tie2 receptor and acts as an antagonistic factor without activating the receptor. Angiopoietin 1 has been considered to be crucial for endothelial sprouting, remodeling of the vessel wall, and recruitment of pericytes and smooth muscle cells. A recent elegant study, however, demonstrated that angiopoietin 1 has different functions depending on the developmental stage and cell type involved [106]. For instance, early embryonic deletion of angiopoietin 1 in mice before E12.5 results in vascular abnormalities that include an increase in the diameter and number of developing vessels without affecting the recruitment of pericytes. On the other hand, deletion of angiopoietin 1 at later stages (after E13.5) did not result in an evident phenotype, but when animals are exposed to injury or microvascular stress there is further organ damage with increased inefficient angiogenesis and fibrosis [106].View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780128001028000138International Review of Cell and Molecular BiologyJ.R. Whiteford, ... A. Woodfin, in International Review of Cell and Molecular Biology, 20162.1.3 Angiopoietin/Tie-2 SystemAngiopoietins are vascular growth factors that support embryonic vasculogenesis and adult-angiogenesis. Ang-1 and Ang-2 bind to the receptor tyrosine kinase Tie-2, which is expressed on endothelial cells and some macrophages and neutrophils. Ang-1 is the primary agonist for Tie-2 and binding induces Tie-2 phosphorylation and intracellular signaling. Ang-2 is a competitive antagonist of Ang-1/Tie-2 interactions, with similar binding affinity to Tie-2 but diminished capacity to activate receptor signaling (Fagiani and Christofori, 2013). In adults constitutive Ang-1 expression, largely by pericytes, is antiinflammatory, promotes endothelial survival and maintains EC/pericyte associations, vascular integrity, and homeostasis. Ang-1 can be considered a paracrine switch that controls the transition from inflammatory or angiogenic endothelium to resting endothelium. Activation of Tie-2 by Ang-1 downregulates inflammation by blocking NFκB-regulated expression of inflammatory genes such ICAM-1 or VCAM-1, and limits VEGF-induced permeability by inhibiting phosphorylation of VE-cadherin and subsequent junctional instability (Fagiani and Christofori, 2013; Gavard et al., 2008; Hughes et al., 2003; Imhof and Aurrand-Lions, 2006; Scholz et al., 2015). Ang-2 generation is stimulated by hypoxia, VEGF, FGF, and various proinflammatory endothelial activators, and its expression is mainly restricted to sites of vascular remodeling. Preformed stores are released from Weibel–Palade bodies in response to endothelial activation, decreasing the environmental ratio of Ang-1/Ang-2 (Fiedler et al., 2004). Autocrine Ang-2/Tie-2 binding on endothelial cells supresses Ang-1 signaling and allows the endothelium to respond to destabilizing and angiogenic signals. Ang-2 promotes loss of endothelial junction integrity, vessel destabilization, increased permeability and detachment of mural cells. See Fig. 2 for a summary of this process. These changes permit tissue infiltration of proteases, cytokines, and myeloid cells, and liberate endothelial tip and stalk cells from the parent vessel to begin migration and proliferation. Ang-2 stimulation of vessels induces endothelial apoptosis, but in the presence of VEGF apoptosis is prevented and the unstable blood vessels begin to develop and grow, suggesting that it is the balance of Ang1/Ang2/VEGF that controls angiogenesis (Fagiani and Christofori, 2013; Murdoch et al., 2007; Scholz et al., 2015).Figure 2. The Angiopoietin/Tie-2 system in quiescent vessels constitutive of Ang-1 produced by pericytes activates Tie-2 signaling, inhibiting the expression of proinflammatory adhesion molecules and blocking VE-cadherin phosphorylation induced permeability. Ang1/Tie-2 signaling promotes endothelial survival and vessel stability. In contrast, in an inflammatory and/or hypoxic environment proinflammatory mediators activate transcription of genes under the control of NFκB including Ang-2. Ang-2 competitively binds Tie-2, inhibiting Ang-1/Tie-2 signaling and negating its stabilizing effects. In parallel to this, hypoxic VEGF expression by endothelial cells and leukocytes exerts mitogenic and migratory effects on the endothelium. The vessel destabilizing effects of Ang-2 in concert with the proliferative and migratory effects of VEGF lead to vessel sprouting and angiogenesis.Adapted from Fig. 2 in Imhof and Aurrand-Lions (2006).In addition to its autocrine role in blocking Ang-1/Tie-2 signaling in the endothelium Ang-2 is also chemotactic for Tie-2 expressing leukocytes. Ang-2, Ang-1, and VEGF promoted recruitment of monocytes and neutrophils to subcutaneous Matrigel sponges, which was associated not only with more angiogenic infiltration but a more mature vessel morphology as quantified by association of α-smooth muscle actin positive cells with the vessels (Sinnathamby et al., 2015). A subset of human blood monocytes express Tie-2 and migrate toward Ang-2 in vitro and in hypoxic tumors where Ang-2 is significantly upregulated (Murdoch et al., 2007; Venneri et al., 2007). This monocyte/macrophage (mo/ma) subset is highly proangiogenic via paracrine mechanisms and is reported to account for most of the proangiogenic activity of myeloid cells in several tumor models (De Palma et al., 2005). Ang-2 has often been viewed simply as an agonist for Ang-1/Tie-2 signaling and was not thought to activate intracellular signaling itself. However, in tumor-associated macrophages, which are exposed to high concentrations of Ang-2, there is evidence of Ang-2 induced Tie-2 phosphorylation. Ang-2 signaling markedly enhanced the proangiogenic activity of Tie-2 expressing macrophages, inducing a tumor-promoting phenotype through the increased expression of the proangiogenic enzymes, thymidine phosphorylase and cathepsin B (Coffelt et al., 2010). Angiopoietins can directly activate neutrophils through Tie-2 signaling to modulate platelet-activating factor synthesis, β2-integrin functional upregulation, and p-selectin translocation, resulting in increased neutrophil adhesion (Lemieux et al., 2005). Endothelial overexpression of Ang-2 induces β2-integrin dependent monocyte adhesion to ICAM-1 and VCAM-1, and promotes accumulation of myeloid cells in various organs (Scholz et al., 2011).Ang-2 signaling works synergistically with proinflammatory mediators to promote angiogenesis, and the existence of preformed stores of Ang-2 in Weibel–Palade bodies suggests roles in rapid vascular responses. Ang-2 release also supports acute inflammatory responses by sensitizing endothelial cells to TNF and promoting endothelial expression of ICAM-1 and VCAM-1, which enhances leukocyte rolling and adhesion. This sensitizing effect of Ang-2 was reversed by Ang-1, indicating that it is likely mediated by endothelial expressed Tie-2 (Fiedler et al., 2006; Imhof and Aurrand-Lions, 2006). In another study TNF induced Ang-2 expression, and in combination with TNF induced enhanced corneal angiogenesis. In the absence of Ang-2, however, TNF did not promote angiogenesis. Interestingly this study also showed that Ang-2 was protective against endothelial apoptosis in the presence of high doses of TNF (Coffelt et al., 2010). Ang-1 and Ang-2 potentiate CXCL8-mediated neutrophil migration via PI-3K activation, demonstrating an ability to enhance neutrophil responses to other cytokines (Brkovic et al., 2007).In summary, Ang-2 has direct proangiogenic effects on endothelial cells, and indirect effects mediated by recruitment of Tie-2 expressing proangiogenic leukocyte subsets or by increasing general leukocyte recruitment via endothelial activation and synergistic enhancement of the proangiogenic and inflammatory effects of other mediators.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/S193764481630048XInterventional NeuroradiologyYao Yao, ... Hua Su, in Handbook of Clinical Neurology, 2021Other factorsOther angiogenic factors have also been implicated in CCM pathogenesis. For example, the loss of CCM3 increases angiopoietin-2 release from brain endothelial cells. Increased angiopoietin-2 secretion to the extracellular space disrupts the association between endothelial cells and pericytes (Zhou et al., 2016), thus leading to enhanced endothelial cell sprouting and lumen formation, which in turn cause CCM lesion formation. CCM3 also may affect tight junctions by indirect interaction with CCM1. CCM3 maintains the cell junction by inhibiting ERK1/2 phosphorylation. Loss of CCM3 can disrupt the tight junction protein complex (Stamatovic et al., 2015).Loss of both CCM1 and CCM2 increases phosphorylation of ERK1/2 (Wustehube et al., 2010; Zhu et al., 2010), which is also downstream of VEGFR2 (Koch et al., 2011). Loss of CCM1 or CCM2 leads to an increase in active c-jun N-terminal kinase (JNK) (Gibson et al., 2015). The activation of JNK in CCM1-depleted cells is mediated by reactive oxygen species, which can be activated by VEGF signaling (Monaghan-Benson and Burridge, 2009), or activate VEGF signaling (Warren et al., 2014).Interestingly, loss of Ccm1 from endothelial cells in mice induced endothelial-to-mesenchymal transition (EndMT), which was mediated by BMP6 and activated TGFβ and BMP signaling (Maddaluno et al., 2013). Inhibitors of these pathways prevented EndMT both in vitro and in vivo, and reduced the number and size of vascular lesions in Ccm1-deficient mice (Maddaluno et al., 2013).In summary (Fig. 4.5), increased VEGF level enhances the impairment of BBB integrity in CCMs. Upregulated Dll4-Notch signaling exacerbates angiogenesis in CCM.Fig. 4.5. Summary of mutations and major angiogenic factors involved in CCM pathogenesis.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780444640345000055Acute Respiratory Distress SyndromeRachel L. Zemans, in Lung Epithelial Biology in the Pathogenesis of Pulmonary Disease, 201710.2.4.4 Additional MediatorsClearly, there are additional mediators that induce epithelial cell injury, such as TGFβ [227] and angiopoietin 2 [228]. Severe hypoxia may also be a mechanism driving alveolar epithelial cell apoptosis in the setting of ARDS [229]. Hypoxia may impair junctional integrity [230] and induce apoptosis [229], leading to epithelial permeability [231], although HIF can also protect against apoptosis [232]. There are also endogenous mechanisms in place that limit epithelial injury. For example, proresolving lipids, critical for the resolution of inflammation [233] have recently been shown to limit alveolar epithelial cell apoptosis [234], as has survivin [235]. Growth factors such as keratinocyte growth factor (KGF) [236] and granulocyte macrophage colony stimulating factor (GMCSF) [237,238] protect against epithelial cell death. Hyaluronan expressed on the epithelial cell surface limits epithelial cell apoptosis, contributing to recovery of the epithelial barrier after lung injury [239].View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780128038093000105Biomarkers in Acute Kidney InjuryC.L. Edelstein MD, PhD, in Biomarkers of Kidney Disease (Second Edition), 2017ANG-2Endothelial activation is an early event in the pathogenesis of microcirculatory dysfunction, capillary leakage, and multiorgan dysfunction syndrome. Angiopoietin-2 (Ang-2), is a circulating antagonistic ligand of the endothelial-specific Tie2 receptor and has been identified as an important gatekeeper of endothelial activation. It was determined whether Ang-2 was as an outcome-specific biomarker in 117 critically ill patients requiring RRT in the ICU [188]. It was determined that circulating Ang-2 is a strong and independent predictor of mortality in dialysis-dependent ICU patients [188].View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780128030141000066New Insights into the Developmental Mechanisms of Coronary Vessels and EpicardiumYuji Nakajima, Kyoko Imanaka-Yoshida, in International Review of Cell and Molecular Biology, 20138.4 Stabilization of Vascular Wall by Angiopoietin 1/Tie2 SignalingThe adhesion and dissociation of EC and mural cells are regulated by angiopoietin-1 (Ang-1) and Ang-2, which are ligands for Tie2, on EC (Gaengel et al., 2009; Ward et al., 2004). Tie2 is constitutively expressed in the endothelium throughout embryonic development as well as in the quiescent vasculature in adults (Dumont et al., 1992; Wakui et al., 2006). Ang-1 is predominantly expressed by perivascular and mural cells (Davis et al., 1996; Sundberg et al., 2002; Wakui et al., 2006) and stimulates Tie2 to induce the adhesion of EC and mural cells (Saharinen et al., 2008). Ang-2 is an antagonist of Ang-1 and is primarily expressed by EC at sites of active vascular remodeling (Takakura, 2011). Tie2-null mice lack mural cells (Patan, 1998) and fail to form a hierarchical organization of large and small vessels (Patan, 1998; Sato et al., 1995), suggesting that Tie2 plays a role in the remodeling of vascular plexuses. Similarly, Ang-1 deletion results in a weak association between EC and the surrounding mural cells and matrix (Suri et al., 1996).However, mice subjected to the targeted mutation of tyrosine residue 1100 of Tie2 displayed normal pericyte recruitment to new vessels in spite of their defective hematopoiesis and cardiac development (Tachibana et al., 2005). Furthermore, experiments involving the CKO of Ang-1 suggested that Ang-1 might not be required for pericyte recruitment (Jeansson et al., 2011). Ang-1 and Tie2 do not seem to be directly involved in mural cell recruitment. Conversely, mural-cell-derived Ang-1 is important for blood vessel formation and/or stability (Thurston et al., 2005; Uemura et al., 2002).View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780124076976000076Acute Hypoxemic Respiratory Failure and ARDSWarren L. Lee MD, PhD, Arthur S. Slutsky MD, in Murray and Nadel s Textbook of Respiratory Medicine (Sixth Edition), 2016Angiopoietins.Angiopoietins are peptides involved in embryonic vascular development. Of the four angiopoietins that have been identified, angiopoietin 1 and angiopoietin 2 (ANGPT1 and ANGPT2, respectively) are the best described. ANGPT1 is expressed by numerous cell types while ANGPT2 is mostly limited to endothelial cells. Both act on the TIE2 receptor tyrosine kinase that is found predominantly on endothelial cells and hematopoietic stem cells.99 A number of observations have generated interest in the potential role of these proteins in the pathophysiology of ARDS. First, elevated levels of ANGPT2 have been described in patients with sepsis and ARDS100 and its administration to mice causes pulmonary vascular leak.101,102 The effect of ANGPT2 in disrupting endothelial cell integrity could be reversed in vitro by ANGPT1. Second, overexpression of ANGPT1 was protective against both endotoxin-induced septic shock and ALI in mice103; a similar benefit was observed using a synthetic peptide agonist of the TIE2 receptor.38 While the cellular mechanism of these effects remains uncertain and is the subject of intense investigation,104,105 the data to date emphasize the important role for endothelial cells in the development of and recovery from ARDS.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9781455733835001007Advances in ParasitologyNicholas M. Anstey, ... Ric N. Price, in Advances in Parasitology, 201211.1.6 Endothelial activation and altered thrombostasisConcentrations of circulating endothelial activation markers are as high (ICAM-1 and E-selectin) or higher (angiopoietin-2) in uncomplicated vivax malaria than in falciparum malaria (Yeo et al., 2010a; Jakobsen et al., 1994). Endothelial dysfunction and impaired NO bioavailability are significant contributors to severe falciparum malaria (Yeo et al., 2007, 2009, 2010b), but their importance in severe vivax malaria is not known. Autopsies in fatal cases of P. vivax malariotherapy of neurosyphilis demonstrated endothelial ‘stimulation’(Bruetsch, 1932a; Clark and Tomlinson, 1949), and endothelial activation and damage has been described in fatal vivax-associated ARDS (Valecha et al., 2009). With the reduced ability of P. vivax to cytoadhere, pathogenic consequences of endothelial activation in promoting sequestration of parasitized red cells will be much less in vivax malaria than in falciparum malaria.However, other consequences of endothelial activation and altered thrombostasis may be more important in P. vivax infection. Elevated von Willebrand factor (VWF) and reduced ADAMTS-13 have been associated with disease severity in falciparum malaria (Larkin et al., 2009; Lowenberg et al., 2010). Increased procoagulant activity (Hemmer et al., 2006), VWF (de Mast et al., 2008) and ADAMTS-13 deficiency (de Mast et al., 2008) have now been reported in uncomplicated vivax malaria. The role of altered haemostatic pathways, intravascular coagulation and endothelial inflammation through increased formation of ultra-large VWF and platelet aggregates in severe vivax malaria is not known. However, with the reports of thrombotic microangiopathy in some cases, vivax-associated kidney disease (Sinha et al., 2012; Saharan et al., 2008; Sharma et al., 1993), these processes may contribute to at least a proportion of vivax associated AKI, coma, anaemia and/or thrombocytopenia.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780123979001000037mTOR as a Modulator of Metabolite Sensing Relevant to AngiogenesisSoumyaS.J. , ... SudhakaranP.R. , in Molecules to Medicine with mTOR, 201614.3.2 Angiopoietin/Tie SignalingAngiopoietin/Tie signaling maintains vascular quiescence and homeostasis of vessels by promoting EC survival and vascular maturation. Ang/Tie signaling comprises Ang1, Ang2, Tie1, and Tie2. Ang1/Tie2 stimulates deposition of basement membrane and thereby vessel maturation through the activation of the ERK/MAPK pathway and PI3K-Akt pathway [23]. Conversely, Ang2 competes with Ang1 for binding to Tie2 and destabilizes vasculature [24]. But the inhibitory effect of Ang2/Tie2 on vessel leakage has also been reported [25]. It appears that the activity of Ang2 may depend on the activation state of endothelium. The function of the Tie1 receptor is to modulate the activity of Tie2 [26].View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780128027332000141Recommended publicationsInfo iconSeminars in Oncology NursingJournalJournal of the American College of CardiologyJournalBrowse books and journalsAbout ScienceDirectRemote accessShopping cartAdvertiseContact and supportTerms and conditionsPrivacy policyWe use cookies to help provide and enhance our service and tailor content and ads. By continuing you agree to the use of cookies.Copyright © 2021 Elsevier B.V. or its licensors or contributors. ScienceDirect ® is a registered trademark of Elsevier B.V.ScienceDirect ® is a registered trademark of Elsevier B.V.