Alternative titles; symbols
HGNC Approved Gene Symbol: ANGPT2
Cytogenetic location: 8p23.1 Genomic coordinates (GRCh38) : 8:6,499,632-6,563,245 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p23.1 | Lymphatic malformation 10 | 619369 | Autosomal dominant | 3 |
Angiopoietin-2 (ANGPT2) is a naturally occurring antagonist of angiopoietin-1 (ANGPT1; 601667) that competes for binding to the TIE2 receptor (600221) and blocks ANGPT1-induced TIE2 autophosphorylation during vasculogenesis (Kim et al., 2000).
By homology screening, Maisonpierre et al. (1997) identified a relative of ANGPT1, termed angiopoietin-2 (ANG2) by them, and showed that it is a naturally occurring antagonist for both ANGPT1 and TIE2. The investigators found that the predicted ANGPT2 protein is 496 amino acids long and has a secretion signal peptide. Human and mouse ANGPT2 are 85% identical in amino acid sequence and approximately 60% identical to their ANGPT1 homologs. Transgenic overexpression of ANGPT2 in mice disrupted blood vessel formation in the mouse embryo. In adult mice and humans, they found that ANGPT2 is expressed only at the sites of vascular remodeling. Maisonpierre et al. (1997) commented that natural antagonists for vertebrate receptor tyrosine kinases are atypical; thus, the discovery of a negative regulator acting on TIE2 emphasized the need for exquisite regulation of this angiogenic receptor system.
By PCR analysis on human umbilical vein endothelial cell cDNA using ANG2-specific primers, Kim et al. (2000) isolated a cDNA encoding a splice variant of ANG2. They termed the splice variant ANG2(443) because the 443-amino acid protein lacks 53 amino acids found in the full-length ANG2 protein. The missing residues, amino acids 96 to 148, are encoded by exon B of the ANG2 gene and include part of the N-terminal coiled-coil domain. Sequence analysis predicted that ANG2(443) is a secreted glycoprotein that retains 4 of the 6 potential N-glycosylation sites present in ANG2. Western blot analysis showed that ANG2 and ANG2(443) are expressed as homodimeric 68- and 61-kD proteins that are reduced to 57 and 51 kD, respectively, after deglycosylation. Binding analysis demonstrated that ANG2(443), like ANG2 and ANG1, binds TIE2 but not TIE1 (600222). The truncated ANG2(443) protein partially inhibits ANG2 and ANG1 binding to TIE2 as well as ANG1-induced phosphorylation of TIE2. RT-PCR analysis showed that expression of ANG2 is approximately 10-fold greater than that of ANG2(443) in primary endothelial cell lines; tumor cell lines had various expression patterns. The authors found that primary lung macrophages express mainly ANG2 and little ANG2(443).
Ward et al. (2001) determined that the ANGPT2 gene contains 9 exons and spans 32.3 kb. Exons 1 to 5 encode the N terminus, the coiled-coil domain, and part of the hinge region, and exons 5 to 9 encode the remainder of the hinge region, the fibrinogen (see 134820)-like domain, and the C terminus.
By FISH and radiation hybrid analysis, Cheung et al. (1998) mapped the human ANGPT2 gene to 8p23. By FISH, Valenzuela et al. (1999) mapped the ANGPT2 gene to 8p21 in a region of syntenic homology on mouse chromosome 8, where the Angpt2 gene was mapped. Using radiation hybrid analysis and FISH, Grosios et al. (1999) mapped the ANGPT2 gene to chromosome 8p23.1.
Tanaka et al. (1999) investigated angiopoietin expression in 23 samples of hepatocellular carcinoma (HCC) and paired adjacent uninvolved liver samples to determine if these genes have a potential role in the growth and spread of the malignancy. They obtained the full coding sequence of a variant angiopoietin-2 cDNA from HCC specimens, and the biologic consequences of overexpression on tumor formation and hemorrhage were determined in an animal model system. Angiopoietin-1 was equally expressed in HCC and adjacent noncarcinomatous liver tissue. On the other hand, angiopoietin-2 was found to be highly expressed only in tumor tissue. In addition, angiopoietin-2 was expressed in 10 of 12 hypervascular HCCs, but only in 2 of 11 hypovascular HCCs. Ectopic expression of angiopoietin-2 in nonexpressing HCC cells promoted the rapid development of human hepatomas and produced hemorrhage within tumors in nude mice. These results suggested a role for angiopoietin-2 in the neovascularization of HCC. The enhanced gene expression may contribute to the clinical hypervascular phenotype as well as to tumor formation and progression.
To explore the possibility that VEGF and angiopoietins collaborate during tumor angiogenesis, Holash et al. (1999) analyzed several different murine and human tumor models. Holash et al. (1999) noted that angiopoietin-1 was antiapoptotic for cultured endothelial cells and expression of its antagonist angiopoietin-2 was induced in the endothelium of co-opted tumor vessels before their regression. Expression of Ang2 continued to mark not only the few surviving internal vessels but also the angiogenic vessels at the tumor margin, suggesting that the destabilizing action of angiopoietin-2 facilitates the angiogenic action of VEGF at the tumor rim. Holash et al. (1999) examined human glioblastomas. Angiopoietin-2 was not detectable in the normal human brain, but its expression was dramatically induced in co-opted tumor vessels, preceding vessel regression. Holash et al. (1999) implanted rat RBA mammary adenocarcinoma cells into rat brains. Co-opted vessels displayed striking and specific upregulation of angiopoietin-2, which was not detectable in the vessels of adjacent brain tissue. Holash et al. (1999) concluded that their observations indicate that a subset of tumors rapidly co-opts existing host vessels to form an initially well-vascularized tumor mass. Perhaps as part of a host defense mechanism there is widespread regression of these initially co-opted vessels, leading to a secondarily avascular tumor and a massive tumor cell loss. However, the remaining tumor is ultimately rescued by robust angiogenesis at the tumor margin.
Geva et al. (2002) investigated VEGFA, ANGPT1, and ANGPT2 transcript profiles, and the protein products that they encode, in placentas from normotensive pregnancies throughout pregnancy. Quantitative real-time PCR analysis demonstrated that VEGFA and ANGPT1 mRNA increased in a linear pattern by 2.5% (not significant) and 2.8%/week (P = 0.034), respectively, whereas ANGPT2 decreased logarithmically by 3.5%/week (P = 0.0003). ANGPT2 mRNA was 400- and 100-fold higher than that of ANGPT1 and VEGFA, respectively, in the first trimester and declined to 20-fold and 7-fold in the third. In situ hybridization and immunohistochemical studies revealed that VEGFA was localized in cyto- and syncytiotrophoblast and perivascular cells, whereas ANGPT1 and ANGPT2 were only in syncytiotrophoblast and perivascular cells in the immature intermediate villi during the first and second trimesters, and mature intermediate and terminal villi during the third trimester. The authors concluded that these molecules may play important roles in placental biology and chorionic villus vascular development and remodeling in an autocrine/paracrine manner.
Watanabe et al. (2005) investigated the involvement of ANG2 and VEGF in the angiogenesis of proliferative diabetic retinopathy (PDR; see 603933). The vitreous level of ANG2 and VEGF were significantly higher in patients with PDR than in controls, and both ANG2 and VEGR levels in eyes with active PDR were significantly higher than in those with inactive PDR. The vitreous concentration of ANG2 correlated significantly with that of VEGF, suggesting an association of ANG2 and VEGF with angiogenic activity in PDR.
White et al. (2003) generated a nuclease-resistant RNA aptamer that binds and inhibits angiopoietin-2 but not the related Tie2 agonist, angiopoietin-1. Local delivery of this aptamer but not a partially scrambled mutant aptamer inhibited basic fibroblast growth factor-mediated neovascularization in the rat corneal micropocket angiogenesis assay. These in vitro data directly demonstrated that a specific inhibitor of angiopoietin-2 can act as an antiangiogenic agent.
Bell et al. (2001) determined that angiopoietin-2 was 1 of several transcripts upregulated by umbilical vein endothelial cells during capillary morphogenesis in 3-dimensional collagen matrices.
A hallmark of highly malignant gliomas is their infiltration of the brain. Hu et al. (2003) analyzed the large number of primary human glioma biopsies and found high levels of expression of angiopoietin-2 in the invasive areas, but not in the central regions, of those tumors. In the invasive regions where ANG2 was overexpressed, increased levels of matrix metalloproteinase-2 (MMP2; 120360) and increased angiogenesis were also evident. A link between these 2 features was apparent, because stable expression of ANG2 by cultured cells or treatment of several glioma cell lines with recombinant ANG2 in vitro caused activation of MMP2 and acquisition of increased invasiveness. Conversely, MMP inhibitors suppressed ANG2-stimulated activation of MMP2 and ANG2-induced cell invasion. These results suggested that ANG2 plays a critical role in inducing tumor cell infiltration, and that this invasive phenotype is caused by activation of MMP2.
Bhandari et al. (2006) demonstrated that Ang2 expression was induced in lung epithelial cells of wildtype mice during hyperoxia, whereas hyperoxia-induced oxidant injury, cell death, inflammation, permeability alterations, and mortality were ameliorated in Ang2-null mice and siRNA-treated mice. The authors observed that hyperoxia induced and activated the extrinsic and mitochondrial cell death pathways and activated initiator and effector caspases through Ang2-dependent pathways in vivo. Ang2 was found to increase inflammation and cell death during hyperoxia in vivo and to stimulate epithelial necrosis in hyperoxia in vitro. In humans, Bhandari et al. (2006) found that ANG2 was significantly increased in plasma and alveolar edema fluid in adults with acute lung injury compared to controls or patients with hydrostatic pulmonary edema; tracheal ANG2 was also significantly increased in neonates with respiratory distress syndrome who developed bronchopulmonary edema. Bhandari et al. (2006) concluded that ANG2 is a mediator of epithelial necrosis with an important role in hyperoxic acute lung injury and pulmonary edema.
Daly et al. (2006) found that, in addition to being a TIE2 antagonist, ANG2 could function like ANG1 as a TIE2 agonist under certain conditions. Inhibition of phosphatidylinositol 3-kinase (see 171834)/AKT (see 164730) signaling in human and bovine endothelial cells derepressed FOXO1 (FOXO1A; 136533) and induced ANG2 expression. Under these conditions, ANG2 activated TIE2/AKT signaling and provided negative feedback on FOXO1-regulated transcription and apoptosis. Administration or expression of human ANG2 in mice, like ANG1, activated Tie2/Akt signaling, induced Tie2 phosphorylation in heart extracts, repressed expression of Foxo1 target genes, and inhibited vascular leaks, although ANG2 had a weaker effect than ANG1.
Hu et al. (2014) showed that the expression of ANG2 in liver sinusoidal endothelial cells (LSECs) is dynamically regulated after partial hepatectomy. During the early inductive phase of liver regeneration, ANG2 downregulation leads to reduced LSEC TGFB1 (190180) production, enabling hepatocyte proliferation by releasing an angiocrine proliferative brake. During the later angiogenic phase of liver regeneration, recovery of endothelial ANG2 expression enables regenerative angiogenesis by controlling LSEC vascular endothelial growth factor receptor-2 (VEGFR2; 191306) expression. Hu et al. (2014) concluded that the data established liver sinusoidal endothelial cells as a dynamic rheostat of liver regeneration, spatiotemporally orchestrating hepatocyte and LSEC proliferation through angiocrine- and autocrine-acting ANG2, respectively.
In 5 probands with lymphedema malformation-10 (LYMPH10; 619369), Leppanen et al. (2020) identified heterozygous mutations in the ANGPT2 gene. One mutation was a de novo deletion encompassing the entire gene (601922.0001); the other 4 were missense mutations. Three of the missense mutations (see, e.g., 601922.0003) showed loss of function with dominant-negative effects, whereas the fourth (601922.0002) appeared to be hypermorphic. Incomplete penetrance was observed in 2 families. The probands were part of a cohort of 543 index patients with primary lymphedema who were screened for mutations in 28 known lymphedema-associated genes as well as candidate genes.
Gale et al. (2002) found that Angpt2-null mice were born at normal frequencies, but almost all died by 2 weeks of age. Angpt2 was not required during embryonic vascular development, but was required during subsequent postnatal vascular remodeling. Using the neonatal mouse eye as a model of vascular remodeling, Gale et al. (2002) found that angiogenic sprouting and vascular regression, which are normally coupled during vascular remodeling, were disrupted in Angpt2-null mice. Homozygous mutants developed severe chylous ascites and lymphatic dysfunction shortly after feeding, which correlated with abnormal structure and patterning of lymphatic vessels. Gene replacement with Angpt1 completely rescued the lymphatic defects in mice lacking Angpt2, but not the defects in vascular remodeling. Since Angpt1 functions only as a Tie2 activator, and Angpt2 can be either a Tie2 activator or inhibitor depending on the cell type, Gale et al. (2002) concluded that Angpt2 is a Tie2 agonist in lymphatic vessel patterning and a Tie2 antagonist during blood vessel remodeling.
Fiedler et al. (2006) found that Ang2-deficient mice had reduced peritoneal neutrophil counts and lacked clinical symptoms in response to short-term inflammation experiments compared with wildtype mice. The inflammation defect could be prevented by prior administration of Ang2, and soluble Tie2 blocked this rescue. Evaluation of leukocyte rolling and adhesion in Ang2-deficient mice showed that rolling increased and firm adhesion strongly decreased after activation of endothelium with Tnf. In vitro experiments showed that human ANG2 promoted leukocyte adhesion to endothelial cells activated with subsaturating concentrations of TNF and that excess ANG1 inhibited these effects of ANG2. Fiedler et al. (2006) concluded that ANG2 is an autocrine regulator of endothelial cell inflammatory responses.
Shen et al. (2014) generated a conditional knockout mouse model targeting Ang2, and observed that mutant mice showed defective formation of collecting lymphatic vessels, with a significant decrease in lymphatic vessel diameter compared to control mice. There was abnormal smooth muscle cell recruitment to lymphatic capillaries and no formation of lymphatic valves in Ang2-null mice. However, despite the lymphatic abnormalities, the mutant mice did not develop lymphedema.
The paper by Yao et al. (2006) regarding methylglyoxal modification of mSin3A was retracted because the panels in several figures were found to contain errors.
In a Belgian boy (family LE-851) with bilateral edema of the distal lower extremities (LMPHM10; 619369), Leppanen et al. (2020) identified heterozygosity for a de novo deletion encompassing all exons of the ANGPT2 gene. The deletion was not present in either of his unaffected parents.
In an Italian girl and her father (family LE-128) with primary lymphedema (LMPHM10; 619369), Leppanen et al. (2020) identified heterozygosity for a c.896C-T transition in the ANGPT2 gene, resulting in a thr299-to-met (T299M) substitution at a conserved residue within the TIE2 (TEK; 600221)-binding fibrinogen-like domain. The mutation was not found in the unaffected mother or in the gnomAD database. Noting that the T299 residues in the ANGPT2 dimer are located between the integrin alpha-5 (ITGA5; 135620) binding sites, the authors analyzed the effect of the T299M mutant on ITGA5 binding and observed reduced binding compared to wildtype. In addition, the T299M mutant was transfected into the ears of 6-week-old mice, which showed enlarged lymphatic vessels with dense sprouting 4 weeks later. There were significant increases in vessel area, width, and skeleton length compared to controls, as well as a slight increase in the number of branching points. The authors concluded that overexpression of the T299M mutant promotes lymphangiogenesis in vivo, consistent with a hypermorphic effect. The affected father and daughter had progression of lymphedema with episodes of cellulitis.
In an Italian boy and his father (family LE-148) with primary lymphedema (LMPHM10; 619369), Leppanen et al. (2020) identified heterozygosity for a c.1304G-C transversion in the ANGPT2 gene, resulting in a cys435-to-ser (C435S) substitution at a conserved residue within the TIE2 (TEK; 600221)-binding fibrinogen-like domain. The mutation was not found in the proband's mother, paternal uncle, or paternal grandmother, or in the gnomAD database; DNA was unavailable from the deceased paternal grandfather, who was reported to have had lymphedema of the feet and varicose veins. The proband showed gradual partial resorption of lymphedema, whereas his father experienced spontaneous resolution of lymphedema. Analysis of transfected HEK293 cells showed no C435S mutant in the supernatant, in contrast to wildtype protein. Immunofluorescence staining revealed that the C435S mutant resulted in intracellular aggregates in HEK293 cells as well as in endothelial cells. Cotransfection with wildtype ANGPT2 reduced ANGPT2 secretion into the culture medium, suggesting that the mutant made heteromers with wildtype protein that affected secretion or folding, consistent with a dominant-negative effect. In addition, the C435S mutant failed to bind TIE2.
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Yao, D., Taguchi, T., Matsumura, T., Pestell, R., Edelstein, D., Giardino, I., Suske, G., Ahmed, N., Thornalley, P. J., Sarthy, V. P., Hammes, H.-P., Brownlee, M. Methylglyoxyl modification of mSin3A links glycolysis to angiopoietin-2 transcription. Cell 124: 275-286, 2006. Note: Retraction: Cell 128: 625 only, 2007. [PubMed: 16413606] [Full Text: https://doi.org/10.1016/j.cell.2005.11.024]