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

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

Endothelial cells that form the inner layers of both blood and lymphatic vessels are important components of the vascular system and are involved in the pathogenesis of vascular and lymphatic diseases. Angiopoietin (Ang)-Tie axis in endothelial cells is the second endothelium-specific ligand-receptor signaling system necessary for embryonic cardiovascular and lymphatic development in addition to the vascular endothelial growth factor receptor pathway. The Ang-Tie axis also maintains vascular homeostasis by regulating postnatal angiogenesis, vessel remodeling, vascular permeability, and inflammation. Therefore, the dysfunction of this system leads to many vascular and lymphatic diseases. In light of the recent advances on the role of the Ang-Tie axis in vascular and lymphatic system-related diseases, this review summarizes the functions of the Ang-Tie axis in inflammation-induced vascular permeability, vascular remodeling, ocular angiogenesis, shear stress response, atherosclerosis, tumor angiogenesis, and metastasis. Moreover, this review summarizes the relevant therapeutic antibodies, recombinant proteins, and small molecular drugs associated with the Ang-Tie axis.
Angiopoietins ; Endothelial Cells/metabolism* ; Humans ; Lymphatic Diseases ; Lymphatic System/metabolism* ; Receptor, TIE-2/metabolism* ; Signal Transduction ; Vascular Endothelial Growth Factor A

OBJECTIVETo study the expression of angiotensin-2 (Ang-2), Tie-2 and vascular endothelial growth factor receptor-2 (VEGFR-2) in colorectal cancer and analyze their relationship with the occurrence, recurrence, metastasis, angiogenesis and prognosis of colorectal cancer.

METHODSImmunohistochemistry with SP method was used to detect the expressions of Ang-2, Tie-2 and VEGFR-2 in 118 colorectal cancer, 40 adjacent normal tissue and 40 benign colorectal lesion specimens.

RESULTSThe positivity rates of Ang-2, Tie-2 and VEGFR-2 in colorectal cancer tissue were 74.58%, 69.49%, and 61.02%, respectively, significantly higher than those in the adjacent normal tissues (25.00%, 17.50%, and 17.50%, P<0.05) and benign colorectal lesion tissues (35.00%, 32.50%, and 32.50%, P<0.05). The rates of two or three coexpression were significantly higher than that of a single expression in the cancer tissues (61.02% vs 15.25%). The microvascular density (MVD) of colorectal cancer tissues was 31.43∓10.50, significantly higher than that of the adjacent normal tissues (10.61∓3.76) and benign colorectal lesions (16.89∓3.83) (P<0.05). The expressions of Ang-2, Tie-2, and VEGFR-2 were positively correlated with carcinoembryonic antigen (CEA) and MVD (P<0.05). The expression of Ang-2, but not Tie-2 and VEGFR-2, was positively correlated with CA199. Ang-2, Tie-2, and VEGFR-2 expressions showed significant differences between cases with tumor recurrence/metastasis and those without 5 years after radical mastectomy, and were all positively correlated with the 5-year survival rates (P<0.05).

CONCLUSIONAng-2, Tie-2 and VEGFR-2 are involved in the development, invasion, metastasis, and prognosis of colorectal cancer, and play important roles in the angiogenesis of the tumors.

Adolescent ; Adult ; Aged ; Angiopoietin-2 ; metabolism ; Colorectal Neoplasms ; blood supply ; metabolism ; Female ; Humans ; Male ; Middle Aged ; Neovascularization, Pathologic ; metabolism ; Prognosis ; Receptor, TIE-2 ; metabolism ; Vascular Endothelial Growth Factor Receptor-2 ; metabolism ; Young Adult

OBJECTIVE: To investigate the relationship between the expression of Ang2, Tie2 and the angiogenesis of hepatocellular carcinoma in rats. METHODS: Thirty-eight healthy male rats were randomly divided into 3 groups: 5 rats in the control group; 25 rats in the experimental group were equally divided into 5-day, 10-day, 15-day, 20-day, and 25-day groups; the other 8 rats were used as the supplement of the experimental group. An allogenic transplanted rat model of CBRH-7919 hepatocellular carcinoma in situ was established by immunosuppression. The expressions of Ang2 and Tie2 were detected by immunohistochemical staining in cancerous tissues of different developmental stages and liver tissues of the control group. At the same time, microvessel density was determined by anti-CD31 immunohistochemical staining. RESULTS: CBRH-7919 hepatocellular carcinoma models were successfully set up in 24 rats. The expression level of Ang2 and Tie2 in cancerous tissues was much higher than that of liver tissues of the control group (P <0.05). The overexpression of Ang2 was pristine and continuous in different developmental stages. The expressions of Ang2 and Tie2 positively correlated with microvessal density in hepatocellular carcinoma (P<0.05). CONCLUSION The up-regulation of Ang2 and Tie2 may play important roles in the angiogenesis of hepatocellular carcinoma. Ang2 may participate in the start of angiogenesis of hepatocellular carcinoma.
Angiopoietin-2 ; biosynthesis ; genetics ; Animals ; Liver Neoplasms, Experimental ; blood supply ; metabolism ; Male ; Neovascularization, Pathologic ; RNA, Messenger ; genetics ; Random Allocation ; Rats ; Rats, Wistar ; Receptor, TIE-2 ; biosynthesis ; genetics

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

OBJECTIVETo investigate the mechanisms of Buyang Huanwu Decoction (BYHWD) by observing its effects on expressions of angiopoietin-1 (Ang-1) and the endothelial-specific receptor tyrosine kinase (Tie-2) mRNA in damaged region of rats' brain after intracerebral hemorrhage (ICH).

METHODSOne hundred and sixty Sprague-Dawley rats were randomly divided into four groups, 10 in the normal control group, 60 in the sham-operative group, 60 in the ICH model group, and 30 in the BYHWD-treated group. The ICH model was established by injecting collagenase type VII 0.5 U stereotaxically into right globus pallidus. Animals in the BYHWD-treated group were administered orally with BYHWD, while animals in the sham-operative group and the ICH model group were administered orally with equal volume distilled water, and those in the normal control group drank water freely. The positional variations of the expression of Ang-1 and Tie-2 in the sham-operative group and the model group were assayed by immunohistochemistry on dayl, 4, 7, 14, 21 and 28 after modeling, in the meantime, the dynamic changes of Ang-1 and Tie-2 mRNA expressions in all groups were assayed by reverse transcription-polymerase chain reaction (RT-PCR).

RESULTSNo significant expression of Ang-1 and Tie-2 in brain of rats in the normal or the sham-operative group was found during the experiment. In the model group, the Ang-1 and Tie-2 positive micrangio-segments appeared at the edge of clot on day 1 to day 4, they gradually penetrated to hematoma area from day 7; with Ang-1 and Tie-2 mRNA expressed from day 1, but very weak until day 4, showing no significant difference to that on day 1; thereafter, they increased gradually, and reached the peak on day 28 (P <0.05). While the two expressions in the BYHWD treated group reached the peak on day 21, and from day 7 to day 28, they were all significantly higher than those in ICH model group at the corresponding time points (P <0.01).

CONCLUSIONBYHWD can promote the up-regulation of Ang-1 and Tie-2mRNA expressions in brain of intracerebral hemorrhagic rats, which might accelerate the angiogenesis in the reconstruction of microvascular network in the damaged zone, and thus facilitating the repairing of damaged tissue.

Angiopoietin-1 ; genetics ; metabolism ; Animals ; Brain ; drug effects ; metabolism ; Cerebral Hemorrhage ; drug therapy ; genetics ; metabolism ; Disease Models, Animal ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Gene Expression ; drug effects ; Humans ; Male ; Rats ; Rats, Sprague-Dawley ; Receptor, TIE-2 ; genetics ; metabolism

OBJECTIVETo explore the effects of angiopoietins (Ang-1 and Ang-2) and Tie-2 expression on microvessel density (MVD) in gastric cancers.

METHODSBy using semiquantitative RT-PCR, immunohistochemistry and image analysis system, the expression of Ang-1, Ang-2, Tie-2 mRNA and their proteins were detected in 68 primary gastric cancers and their adjacent normal tissues. Microvessel density (MVD) was figured out based on CD34 immunohistochemical staining.

RESULTSThe expression of all Ang-1, Ang -2, Tie-2 mRNA and their proteins was detected in gastric cancers and their paired adjacent gastric mucosa tissues. A negative correlation between Ang-1 protein, Tie-2 mRNA and MVD in gastric cancers was observed (r = -0.440, r = -0.267; P < 0.05), while the relation between Ang-2 mRNA and its protein, Ang-2/Ang-1 protein ratio with MVD were positive (r = 0.319, r = 0.729, r = 0.739; P < 0.05). It was found that MVD in groups with Ang-2 mRNA T/N ratio over 1.2 (the ratio of Ang-2 mRNA in gastric cancers and its adjacent normal mucosa) was higher than that in those with a ratio under 1.2, revealed by analysing the effects of Ang-1 and Ang-2 mRNA T/N ratio on MVD in gastric cancers.

CONCLUSIONAng-1 activates Tie-2 receptor, whereas Ang-2 antagonizes Ang-1 in the angiogenesis, and the Ang-2/Ang-1 ratio determines angiogenesis and tumor growth in gastric cancers. When the expression of Ang-2 is high and Ang-1 is low, the angiogenesis in gastric cancers is promoted, otherwise oppositely. The role of Ang-2 is dominant in the effect of Angs and their receptor on angiogenesis in gastric cancers.

Angiopoietin-1 ; biosynthesis ; genetics ; Angiopoietin-2 ; biosynthesis ; genetics ; Female ; Humans ; Male ; Microcirculation ; pathology ; Middle Aged ; Neoplasm Staging ; Neovascularization, Pathologic ; etiology ; RNA, Messenger ; biosynthesis ; genetics ; Receptor, TIE-2 ; biosynthesis ; genetics ; Stomach Neoplasms ; blood supply ; metabolism ; pathology

Angiopoietin-1 (Ang1) binds to and activates Tie2 receptor tyrosine kinase. Ang1-Tie2 signal has been proposed to exhibit two opposite roles in the controlling blood vessels. One is vascular stabilization and the other is vascular angiogenesis. There has been no answer to the question as to how Tie2 induces two opposite responses to the same ligand. Our group and Dr. Alitalo's group have demonstrated that trans-associated Tie2 at cell-cell contacts and extracellular matrix (ECM)-anchored Tie2 play distinct roles in the endothelial cells. The complex formation depends on the presence or absence of cell-cell adhesion. Here, we review how Ang1-Tie2 signal regulates vascular maintenance and angiogenesis. We further point to the unanswered questions that must be clarified to extend our knowledge of vascular biology and to progress basic knowledge to the treatment of the diseases in which Ang1-Tie2-mediated signal is central.
Angiopoietin-1/*physiology ; Animals ; Cell Adhesion/physiology ; Cell Movement/physiology ; Endothelial Cells/*physiology ; Endothelium, Vascular/physiology ; Extracellular Matrix/*metabolism ; Humans ; Neovascularization, Physiologic/physiology ; Receptor, TIE-2/*physiology ; Signal Transduction/*physiology