Angiopoietins(ANGPT) and their endothelial cell-specific tyrosine kinase receptors TEK are the major regulators of blood vessels angiogenesis under physiological and pathologic conditions. ANGPT1 is essentially involved in maturation, stabilization, and remodeling of blood vessels through inducing TEK autophosphorylation, promoting endothelial cell migration and survival. Instead, ANGPT2 appears to act as a natural antagonist of ANGPT1, it can activate vascular remodeling with the presence of vascular endothelial growth factor(VEGF) or regress frank blood vessels under the absence of VEGF. High expression of angiopoietins and TEK is often detected in tumor tissues. Many studies showed that disrupting the ANGPT/TEK receptor pathway could inhibit the growth of a number of murine tumors and human tumors. Thus, it is possible that inhibitors targeting the ANGPT/TEK pathway will have broad clinical utility to treatment of cancer.
Angiopoietin-1 ; physiology ; Angiopoietin-2 ; physiology ; Angiopoietins ; physiology ; Humans ; Neovascularization, Physiologic ; physiology ; Receptor, TIE-2 ; physiology

BACKGROUND: The Angiopoietin-1 (Ang1), Angiopoietin-2 (Ang2) and Tie2 have essential role in angiogenesis in development. Ang1 and Ang2 are ligands which binds to their receptor, Tie2. METHODS: Expression of these proteins was sought during mouse kidney maturation from embryonic day 16 (E16) to 28 days postnatal (P28). RESULTS: Using RNase protection assay and Western blot, these three molecules were expressed throughout the experimental period with peak levels at P28 (Ang1), P14 (Ang2) and P7 (Tie2). By immunohistochemical analysis, Ang1 protein was found to localize to condensing renal mesenchymal cells, and tubules. Ang2 proteins were detected in differentiating outer medullary tubules and the vasa recta bundle area. Tie2 protein was detected in a portion of glomerular tufts and cortical interstitium, and medulla including vessels in the vasa recta. CONCLUSIONS: These data suggest that Ang1, Ang2 and Tie2 proteins are expressed in renal development.
Angiopoietin-1* ; Angiopoietin-2* ; Animals ; Blotting, Western ; Kidney* ; Ligands ; Mice* ; Receptor, TIE-2 ; Ribonucleases

OBJECTIVETo study the expression of angiopoietin-1 (Ang-1) and its receptor Tie-2 in multiple myeloma (MM) patients and RPMI8226 cells, and analyze the significance of Ang-1 expression and its relevance to the tumorigenes and development of MM.

METHODSRT-PCR and Western blot were used to detect the expression of Ang-1 and Tie-2 in bone marrow (BM) samples from 112 MM patients and 24 control subjects, and in RPMI8226 cells. The expression levels of Ang-1 in different groups and disease stages were analyzed.

RESULTSThe positive rate and expression level of Ang-1 were significantly higher in MM group than in control group (P < 0.05). The positive rates of Ang-1 were not significantly different between newly diagnosed and relapsed/refractory MM groups, but its expression level was significantly higher in the latter group than in the former group (P < 0.05). Tie-2 was detected only in 12 MM patients and did not in control group and RPMI8226 cells. Microvessel density in BM samples were significantly higher in MM group than in control group (25.21 ± 0.80 vs 5.23 ± 0.20, P < 0.01), and were higher in Ang-1-positive MM group than in Ang-1-negative MM group (32.98 ± 1.70 vs 16.55 ± 1.30, P < 0.05). The positive rates of Ang-1 protein were not significantly different between stage II and stage III MM (52.1% vs 60.9%, P > 0.05), but the expression level of Ang-1 protein was higher in stage III than that in stage II MM (0.40 ± 0.07 vs 0.22 ± 0.04, P < 0.05). In the newly diagnosed MM patients, the positive rate of Ang-1 protein in PD patients was significantly higher than in PR and MR patients (70.0% vs 19.1%, P < 0.01).

CONCLUSIONHigh expression of Ang-1 is found in MM patients and RPMI8226 cells, and its expression is associated with the disease stage, prognosis and targeted therapy of MM.

Angiopoietin-1 ; Humans ; Multiple Myeloma ; metabolism ; Prognosis ; RNA, Messenger ; Receptor, TIE-2

PURPOSE: Angiopoietin-1 (Ang-1) plays a crucial role in vascular and hematopoietic development, mainly through its cognate receptor, Tie-2. Increased levels of Ang-2 have been shown to be correlated with abnormal tumor angiogenesis in several malignancies. Hence, we estimated the increased expression of Ang-2 relative to Ang-1 in patients with colorectal cancer and correlated our finding with prognosis in order to investigate the relationships between the expressions of Ang-1/Ang-2/Tie-2 receptor and the clinical parameters or overall survival of such patients. METHODS: We retrospectively analyzed 114 tissue samples from patients with colorectal cancer by using immunohistochemistry (IHC) to examine Ang-1, Ang-2, and Tie-2 expressions and to investigate the relationship between those expressions and clinical parameters or overall survival of such patients. A Western blot analysis was used for Ang-2 expression. RESULTS: IHC staining showed a link between Ang-1 and Tie-2 (P = 0.018), as well as meaningful correlations between Ang-2 and Tie-2 receptor (P = 0.022) and between lymph-node metastasis and Ang-2 (P = 0.025). The stronger the IHC staining for Ang-2 expression was, the shorter the cumulative survival was (P = 0.016). CONCLUSION: A relationship was found to exist between Ang-2 and Tie-2 expressions. The Ang-2 was correlated with lymph-node metastasis, and high expression of Ang-2 was indicative of poor overall survival. These findings suggest that Ang-2 is a useful prognostic marker in the management of patients with colorectal cancer. In addition, we suggest that Ang/Tie-2 signaling plays an important role in the progression of colorectal cancer.
Angiopoietin-1* ; Angiopoietin-2* ; Angiopoietins ; Blotting, Western ; Colorectal Neoplasms* ; Humans ; Immunohistochemistry ; Neoplasm Metastasis ; Prognosis ; Receptor, TIE-2* ; Retrospective Studies

OBJECTIVETo investigate the relationship of angiogenesis and the Ang family members/ receptor (Ang/Tie2) in hemangioma.

METHODSExpression of Ang1, Ang2 and the receptor Tie2 was detected with immunohistochemical SP method and RT-PCR method in 17 cases of proliferating hemangioma, 13 involuting cases and 10 cases of normal children skin.

RESULTSThe expression of Ang2 and Tie2 was higher markedly in proliferating hemangiomas than in involuting hemangiomas (P < 0.01), and was rare or negative in normal skin. Expression of Ang1 was rare or negative both in hemangioma and normal skin without significant difference between them (P > 0.05).

CONCLUSIONAng/Tie2 system may play an important role in the proliferating and involuting process of hemangioma.

Angiopoietin-1 ; metabolism ; Angiopoietin-2 ; metabolism ; Child, Preschool ; Hemangioma ; metabolism ; pathology ; Humans ; Infant ; Receptor, TIE-2 ; metabolism

PURPOSE: It has been reported that angiopoietins and Tie-2 receptor play an important role in the maintenance of glomerular filtration barrier in various glomerulonephritis models. We studied the role of angiopoietins on renal injury in diabetes. METHODS: In this study, we examined the changes of angiopoietin-1, angiopoietin-2, Tie-2 receptor, and nephrin expression in the experimental diabetic nephropathy and also determined whether these changes were modified by renoprotective intervention by angiotensin II receptor blocker, alpha-lipoic acid, and peroxisome proliferator activated receptor (PPAR)-agonist. RESULTS: A marked increase in urinary albumin excretion and glomerular volume was observed in diabetic rats. Renal angiopoietin-2 and Tie-2 receptor expression were significantly higher in diabetic rats than in the control groups, with a significant reduction in renal angiopoietin-2 expression, albuminuria, and renal hypertrophy in angiotensin II receptor blocker-treated diabetic rats. And there was a significant reduction in renal Tie-2 expression and renal hypertrophy in alpha-lipoic acid-treated and PPAR-gamma agonist-treated diabetic rats. CONCLUSION: These results demonstrate that the dysregulation of angiopoietins and Tie-2 receptor can lead to renal hypertrophy and albuminuria. Angiotensin II receptor blocker, alpha-lipoic acid, and PPAR-gamma agonist attenuated these changes in angiopoietins and/or Tie-2 expression and prevented the development of albuminuria and renal hypertrophy in vivo.
Albuminuria ; Angiopoietin-1 ; Angiopoietin-2 ; Angiopoietins* ; Animals ; Diabetic Nephropathies* ; Glomerular Filtration Barrier ; Glomerulonephritis ; Hypertrophy ; Peroxisomes ; Rats ; Receptor, TIE-2 ; Receptors, Angiotensin ; Thioctic Acid

CTHRC1 (collagen triple-helix repeat-containing 1), a protein secreted during the tissue-repair process, is highly expressed in several malignant tumors, including pancreatic cancer. We recently showed that CTHRC1 has an important role in the progression and metastasis of pancreatic cancer. Although CTHRC1 secretion affects tumor cells, how it promotes tumorigenesis in the context of the microenvironment is largely unknown. Here we identified a novel role of CTHRC1 as a potent endothelial activator that promotes angiogenesis by recruiting bone marrow-derived cells to the tumor microenvironment during tumorigenesis. Recombinant CTHRC1 (rCTHRC1) enhanced endothelial cell (EC) proliferation, migration and capillary-like tube formation, which was consistent with the observed increases in neovascularization in vivo. Moreover, rCTHRC1 upregulated angiopoietin-2 (Ang-2), a Tie2 receptor ligand, through ERK-dependent activation of AP-1 in ECs, resulting in recruitment of Tie2-expressing monocytes (TEMs) to CTHRC1-overexpressing tumor tissues. Treatment with a CTHRC1-neutralizing antibody-abrogated Ang-2 expression in the ECs in vitro. Moreover, administration of a CTHRC1-neutralizing antibody to a xenograft mouse model reduced the tumor burden and infiltration of TEMs in the tumor tissues, indicating that blocking the CTHRC1/Ang-2/TEM axis during angiogenesis inhibits tumorigenesis. Collectively, our findings support the hypothesis that CTHRC1 induction of the Ang-2/Tie2 axis mediates the recruitment of TEMs, which are important for tumorigenesis and can be targeted to achieve effective antitumor responses in pancreatic cancers.
Angiopoietin-2 ; Animals ; Carcinogenesis ; Endothelial Cells ; Heterografts ; In Vitro Techniques ; Mice ; Monocytes* ; Neoplasm Metastasis ; Pancreatic Neoplasms ; Receptor, TIE-2 ; Transcription Factor AP-1 ; Tumor Burden ; Tumor Microenvironment

Angiopoietin-1 ; chemistry ; physiology ; Angiopoietin-2 ; chemistry ; physiology ; Angiopoietins ; physiology ; Animals ; Cardiovascular Diseases ; therapy ; Embryonic and Fetal Development ; Humans ; Neoplasms ; blood supply ; Receptor, TIE-2 ; chemistry ; physiology ; Signal Transduction

OBJECTIVETo study the effect of dexamethasone on airway morphology and on the expression of angiopoietin-1 (Ang-1) and its tyrosine kinase receptor Tie-2 in the airway of asthmatic rats.

METHODSForty-five Sprague-Dawley rats were randomly divided into control, asthmatic, and dexamethasone-treated asthmatic groups. Asthma was induced by repeated sensitization and challenge with ovalbumin in the latter two groups. The dexamethasone intervention group received an intraperitonea injection of dexamethasone (2 mg/kg) before asthma challenge. Immunohistochemistry was used to measure the expression of Ang-1 and Tie-2 in the airway. Airway thickness was estimated by a computerized digital image analyzer.

RESULTSAirway thickness in the asthmatic group (33.9333+/-8.3791 micro m2/micro m) increased significantly compared with that in the control group (21.1333+/-2.7740 micro m2/micro m) (P<0.01). The dexamethasone intervention group also showed increased thickness of the airway (27.4000 +/- 4.6105 micro m2/micro m) compared with the control group (P<0.01), but the airway thickness in the dexamethasone intervention group was significantly reduced compared with that in the untreated asthmatic group (P<0.01). The expression of Ang-1 (103.9487+/-8.2914 vs 76.0320+/-3.7728; P<0.01) and Tie-2 (99.2307+/-8.1913 vs 75.3153+/-3.7321; P<0.01) in the airway increased significantly in the asthmatic group compared to controls. The expression of Ang-1 and Tie-2 in the airway of the dexamethasone intervention group (90.6180+/-5.2339 and 86.6633+/-3.7321, respectively) was statistically higher than that in the control group (P<0.01) but statistically lower than that in the untreated asthmatic group (P<0.01). Ang-1 and Tie-2 expression in the airway was positively correlated with the thickness of airway (r(Ang)-1=0.719r(Tie)-2=0.746P<0.01). There was also a positive correlation between Ang-1 and Tie-2 expression (r=0.742P<0.01).

CONCLUSIONSThe expression of Ang-1 and Tie-2 in the airway increased in asthmatic rats and was positively correlated with the thickness of the airway. Ang-1 and Tie-2 may participate in the process of airway remodeling in asthma. Dexamethasone can decrease the expression of Ang-1 and Tie-2 in the airway and relieve the changes of airway morphology.

Angiopoietin-1 ; analysis ; physiology ; Animals ; Asthma ; metabolism ; pathology ; Female ; Lung ; chemistry ; pathology ; Rats ; Rats, Sprague-Dawley ; Receptor, TIE-2 ; analysis ; physiology

The tyrosine kinase system angiopoietin (Ang)/Tie interacts with vascular endothelial growth factor pathway and regulates vessel quiescence in adults as well as later steps of the angiogenic cascade related to vessel maturation. Since all Angs are able to bind to Tie-2 but none binds to Tie-1, the function of Tie-2 and its ligands have captured attention. However, emerging evidence indicates unique roles of the orphan receptor Tie-1 in angiogenesis under physiological and pathological conditions. It is required for maintaining vascular endothelial cell integrity and survival during murine embryo development and in adult and may be involved in modulating differentiation of hematopoietic cells in adult. Tie-1 exhibits poor tyrosine kinase activity and signals via forming heterodimers with Tie-2, inhibiting Tie-2 signaling mediated by Angs. This inhibition can be relieved by Tie-1 ectodomain cleavage mediated by tumor- and inflammatory-related factors, which causes destabilization of vessels and initiates vessel remodeling. Up-regulated Tie-1 expression has been found not only in some leukemia cells and tumor related endothelial cells but also in cytoplasm of carcinoma cells of a variety of human solid tumors, which is associated with tumor progression. In addition, it has pro-inflammatory functions in endothelial cells and is involved in some inflammatory diseases associated with angiogenesis. Recent research indicated that Tie-1 gene ablation exhibited significant effects on tumor blood- and lymph-angiogenesis and improved anti-Ang therapy, suggesting Tie-1 may be a potential target for tumor anti-angiogenesis treatment.
Angiogenesis Inhibitors ; therapeutic use ; Angiopoietins ; genetics ; metabolism ; Animals ; Embryo, Mammalian ; Embryonic Development ; genetics ; Endothelial Cells ; drug effects ; metabolism ; pathology ; Gene Expression Regulation, Developmental ; Gene Expression Regulation, Neoplastic ; Humans ; Mice ; Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; Neovascularization, Pathologic ; drug therapy ; genetics ; metabolism ; pathology ; Protein Binding ; Receptor, TIE-1 ; antagonists & inhibitors ; genetics ; metabolism ; Receptor, TIE-2 ; genetics ; metabolism ; Signal Transduction