Polymorphisms in TIE2 and ANGPT-1 genes are associated with protection against diabetic retinopathy in a Brazilian population

ABSTRACT Objective: The objective of this study was to investigate the association between SNPs in the TIE2 and ANGPT-1 genes and diabetic retinopathy (DR). Subjects and methods: This study comprised 603 patients with type 2 diabetes mellitus (T2DM) and DR (cases) and 388 patients with T2DM for more than 10 years and without DR (controls). The TIE2 rs639225 (A/G) and rs638203 (A/G) SNPs and the ANGPT-1 rs4324901 (G/T) and rs2507800 (T/A) SNPs were genotyped by real-time PCR using TaqMan MGB probes. Results: The G/G genotype of the rs639225/TIE2, the G/G genotype of the rs638203/TIE2 and the T allele of the rs4324901/ANGPT-1 SNPs were associated with protection against DR after adjustment for age, glycated hemoglobin, gender, and presence of hypertension (P = 0.042, P = 0.003, and P = 0.028, respectively). No association was found between the rs2507800/ANGPT-1 SNP and DR. Conclusion: We demonstrated, for the first time, the association of TIE2 rs638203 and rsrs939225 SNPs and ANGPT-1 rs4324901 SNP with protection against DR in a Brazilian population.

Effect of propranolol on angiopoietin and Tie2 in nude mice model with hemangioma / 中华医学美学美容杂志

Objective:To investigate the effect of propranolol on angiopoietin and its receptor in the nude mouse model of infantile hemangioma, so as to clarify the mechanism of propranolol in the treatment of hemangioma.Methods:The proliferative hemangioma tissue from the 980 Hospital of PLA was transplanted into the back of 50 female nude mice during May 2015 to Sept. 2016. After establishment of the hemangioma model, the nude mice were randomly divided into two groups, 25 in each group. The experimental group was gavaged with 0.4 ml propranolol every 2 days, and the control group was gavaged with normal saline every 2 days. The mice were killed in batches on the 7th, 14th, 21st and 28th day, the tumor morphology was observed by HE staining. The expression of VEGF, Ang1, Ang2 and Tie2 protein in hemangiomas was detected by immunohistochemistry and Western blot.Results:After 28 days, the hemangioma in propranolol group showed regression phase. The endothelial cells of hemangioma decreased, and the nuclear staining became shallow, the lumen enlarged, and fibrous connective tissue could be seen between the blood vessels. The expression of VEGF, Ang2 and Tie2 was lower than those in the control group ( P<0.05), and the expression of VEGF, Ang2 and Tie2 was decreased by 47.1%, 34.7% and 37.5%, respectively, while the expression of Ang1 was increased by 40.5% compared with the control group ( P<0.05). Conclusions:Propranolol may inhibit the growth of hemangioma in nude mice by promoting the expression of Ang1 and inhibiting the expression of VEGF, Ang2 and Tie2.

Advances of Angiopoietin-Tie axis in vascular and lymphatic system-related diseases / 生物工程学报

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.

Tie2 Expressing Monocytes/Macrophages in Human Tumors / 肿瘤防治研究

Tie2 expressing monocytes/macrophages (TEMs) are a subtype of monocytes or macrophages which expressing tyrosine kinase receptor Tie2. They can exist in peripheral blood and tissues of both human and mouse. TEMs can participate in the formation of tumor microenvironment by accelerating tumor angiogenesis, lymphangiogenesis and immunosuppression. At present, TEMs have been found to have potential diagnostic and prognostic guiding significance for a variety of tumors, and they are expected to provide new directions and strategies for tumor therapy. This paper reviews the research progress of TEMs in tumor.

Engeletin protects against cerebral ischemia/reperfusion injury by modulating the VEGF/vasohibin and Ang-1/Tie-2 pathways

Engeletin is a natural derivative of Smilax glabra rhizomilax that exhibits anti-inflammatory activity and suppresses lipid peroxidation. In the present study, we sought to elucidate the mechanistic basis for the neuroprotective and pro-angiogenic activity of engeltin in a human umbilical vein endothelial cells (HUVECs) oxygen-glucose deprivation and reoxygenation (OGD/R) model system and a middle cerebral artery occlusion (MCAO) rat model of cerebral ischemia and reperfusion injury. These analyses revealed that engeletin (10, 20, or 40 mg/kg) was able to reduce the infarct volume, increase cerebral blood flow, improve neurological function, and bolster the expression of vascular endothelial growth factor (VEGF), vasohibin-2 (Vash-2), angiopoietin-1 (Ang-1), phosphorylated human angiopoietin receptor tyrosine kinase 2 (p-Tie2), and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) in MCAO rats. Similarly, engeletin (100, 200, or 400 nM) markedly enhanced the migration, tube formation, and VEGF expression of HUVECs in an OGD/R model system, while the VEGF receptor (R) inhibitor axitinib reversed the observed changes in HUVEC tube formation activity and Vash-2, VEGF, and CD31 expression. These data suggested that engeletin exhibited significant neuroprotective effects against cerebral ischemia and reperfusion injury in rats, and improved cerebrovascular angiogenesis by modulating the VEGF/vasohibin and Ang-1/Tie-2 pathways.

Expression of Serum Vascular Endothelial Growth Factor and Angiopoietin Receptor Tie-2 in Essential Hypertension

ABSTRACT Objective: To investigate the serum levels of a vascular endothelial growth factor (VEGF), an angiogenic factor and a soluble angiopoietin receptor Tie-2 (sTie-2) in patients with essential hypertension. Methods: In the present study 90 individuals (56 males and 34 females, mean age 48 ± 7 years) have been divided into 3 groups: 30 patients with hypertension, 30 healthy individuals with a family history of hypertension and 30 healthy individuals with no family history of hypertension. All individuals have been evaluated in terms of blood pressure and biochemical parameters. The levels of VEGF and Tie-2 receptor have been evaluated by using the enzyme-linked immunosorbent assay method. Results: The findings suggested that the serum VEGF, sTie-2 receptor, low-density lipoprotein and triglycerides levels in the hypertensive patients were significantly higher than those in the control group (p < 0.05). However, the level of high-density lipoprotein cholesterol in the patients was significantly lower than in those in the control group (p < 0.05). In correlation analysis, a positive correlation was found statistically significant between the values of VEGF and sTie-2 (r = 0.405, p = 0.026). Conclusion: As a result of this study, our data indicate that serum levels of VEGF and Tie-2 receptor may be related to the primary hypertension. This study could inspire to further studies to explore the roles of VEGF and Tie-2 receptor in essential hypertension.

Experimental study on B7-H3 + Tie2 expressing monocytes mediated angiogenesis in clear cell renal cell carcinoma / 中华泌尿外科杂志

Objective To explore the role of B7-H3 in the Tie2 expressing monocytes (TEMs) mediated angiogenesis of clear cell renal cell carcinoma (ccRCC).Methods Level of B7-H3 expression on TEMs surface was detected by flow cytometry in ccRCC tissues and normal renal tissues,which were obtained from April 2016 to August 2016 from 20 patients.Microvessel density (MVD) labeled by CD34 in high B7-H3 + TEMs group and low B7-H3 + TEMs group was detected by immunohistochemical examination in ccRCC specimens.B7-H3 + TEMs and B7-H3-TEMs were co-cultured with the 786-O cell lines,and B7-H3 + TEMs and B7-H3-TEMs culture supernatants were collected as conditioned medium,then the effect of B7-H3 + TEMs on angiogenesis was tested by tubule formation assay and mouse aortic ring assay.Results Flow cytometry showed that the frequency of B7-H3 expression on TEMs in ccRCC was (45.10 ± 17.78)％,and the frequency of B7-H3 expression in normal kidney tissues was (10.28 ± 4.28) ％.The frequency of B7-H3 expression on TEMs was significantly higher than that in normal renal tissues (P ＜ 0.001).The MVD of high B7-H3 + TEMs group (103.81 ± 29.28) was higher than that of low B7-H3 + TEMs group (76.55 ± 20.80) (P =0.027).The results of tube formation assay showed that the number of tubule formation of HUVEC in B7-H3 +TEMs group(55.25 ± 11.48) was significantly greater than that of B7-H3-TEMs group (31.34 ± 8.45) and blank control group (25.00 ± 6.74) (P ＜ 0.001).The results of mouse aortic ring assay showed that the number of neovascularization in B7-H3 + TEMs group(77.35 ± 18.47) was significantly greater than that of B7-H3-TEMs group (39.42 ± 8.29) and blank control group (28.79 ± 7.63) (P ＜0.001).Conclusions B7-H3 + TEMs can promote angiogenesis in ccRCC,and might act as an effective target in anti-angiogenic therapy for ccRCC.

Diagnosis value of peripheral blood TEMs percentage in the AFP negative early hepatocellular carcinoma / 中华检验医学杂志

Objective To evaluate the diagnosis value of the percentage of Tie 2-expressing monocytes(TEMs)in CD14+CD16+monocytes of peripheral blood from hepatocellular carcinoma(HCC) patients with negative AFP and tumor size≤3 cm.Methods Flow Cytometry(FCM)was used to determine the percentage of TEMs in CD14+CD16+monocytes of peripheral blood from patients with HCC(n=82), liver cirrhosis(n=29), chronic hepatitis B(n=28), and healthy controls(n=31).Abbott i2000 microparticle chemiluminescence immunoassay analyzer was used to determine the plasma alpha -fetoprotein (AFP)levels.The difference among multi groups was analyzed by the Kruskal-Wallis H test.Two independent groups were analyzed by the Mann-Whitney U test.The chi-square test was used in the rate comparison.The correlation between TEMs and AFP was analyzed by Spearman rank correlation analysis. Morever, the areas under the receiver operating characteristic curves(ROC-AUC), sensitivity and specificity of TEMs or AFP in differentiating HCC, HCC with AFP negative or tumor size≤3 cm were analyzed.Results The percentage of TEMs in CD14 +CD16 +monocytes of peripheral blood from HCC or HCC with negative AFP or HCC with tumor size≤3 cm was significantly higher than that in patients with liver cirrhosis,chronic hepatitis B and healthy controls(P<0.05).ROC-AUC of TEMs and AFP in the diagnosis of HCC were 0.701(95% CI 0.626-0.768)and 0.712(95% CI 0.638-0.779) respectively.When the cut-off values of TEMs and AFP were 4.95%and 20 μg/L,the sensitivities of TEMs and AFP were 71.95%and 45.12%,and the specificities of TEMs and AFP were 70.45%and 85.23%. The sensitivity of TEMs in the diagnosis of HCC was significantly higher than that of AFP(χ2=12.16,P=0.000).The specificity of AFP was significantly higher than that of TEMs(χ2=5.57,P=0.018).There was a highest sensitivity(89.02%)in TEMs/AFP method,and there was a highest specificity(93.18%) in TEMs+AFP method in the diagnosis of HCC.There was no significant difference between the ROC-AUC for the TEMs and the AFP in the diagnosis of 26 patients with tumor size≤3 cm HCC(0.776 vs 0.645,Z=1.805,P=0.071),TEMs/AFP had the highest sensitivity(84.62%),while TEMs+AFP had the highest specificity(93.18%)in the diagnosis of tumor size≤3cm HCC.The ROC-AUC for the TEMs in the diagnosis of 45 patients with AFP negative HCC was 0.739(95%CI 0.648-0.829).The sensitivity and specificity of TEMs were 80.0% and 70.45% respectively.There was no correlation between the level of plasma AFP and the percentage of TEMs(r=-0.169, P=0.129)determined by Spearmans rank correlation coefficient.Conclusions TEMs is valuable in the diagnosis of HCC with negative AFP and tumor size≤3cm,and the two tests of TEMs and AFP can complement each other in the diagnosis of patients with HCC.

Expressions and Clinical Significances of Angiopoietin-1, Angiopoietin-2, and Tie-2 Receptor in Patients With Colorectal Cancer

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.

Research progress in relationship between angiogenin-Tie2 signaling pathways and sepsis / 国际儿科学杂志

Angiopoietin(Ang)is a secreted endothelial cell specific growth factor.Ang 2 levels in the body increase in bloodstream during infection.Studies have demonstrated that Ang 2 is a potential therapeutic target in sepsis.This paper reviews the biological function of Ang 2-Tie2 and Ang 2 inhibitors for a potential role of sepsis treatment.

The expression changes of peripheral endothelial progenitor cells and Ang-1/Tie2 in patients with pulmonary arterial hypertension / 中华检验医学杂志

Objective To observe the expression changes of peripheral endothelial progenitor cells (EPCs) and Ang-1/Tie2 in patients with pulmonary arterial hypertension (PAH).Methods From Jun 2011 to Dec 2012,45 patients with PAH charged in Affiliated Hospital of Hangzhou Normal University were divided into 3 groups according to mean pulmonary arterial blood pressure (15 per group):mild(Group L),moderate(Group M),and severe(Group S),with another 15 normal people as control group(Group C).The EPCs were isolated from peripheral blood of every patient,number counting using fluorescence activated cell sorter (FACS),function test using cell culture in vitro.Expression of Ang-1 and Tie2 in the peripheral EPCs were measured by RT-PCR or Western-blot.Non normal data was analyzed by non parametric statistical test.Results The statistical discrepancy existed among Group L,M,S and the control in the number of EPCs [32.0 (27.0,37.0),26.0 (19.0,31.0),24.0 (22.0,26.0) vs 40.0 (37.0,51.0),P ＜ 0.05].The ability of migration [32.1 (26.5,37.5),26.8 (22.4,35.4),21.0 (17.8,34.0) vs 39.0 (33.3,42.4),P＜0.05] and adhesion of the EPCs [57.1(50.9,61.8),51.8(45.2,58.7),46.0 (37.2,55.1) vs 64.1 (56.2,75.0),P ＜ 0.05] among study groups and control group was different in statistic,the same with the proliferation activity of EPCs in different groups [0.6 (0.5,0.7),0.5 (0.4,0.6),0.4(0.3,0.5) vs 0.7(0.6,0.8),P ＜0.05].The mRNA expression of Ang-1 and Tie2 in Group M & S were significantly reduced compared with control [4.33 (2.49,4.62) and 2.89 (2.39,3.44) vs 5.31(3.78,6.22),P＜0.05],Tie2 mRNA[1.32(1.23,1.34)and 1.23(1.08,1.42)vs 1.49(1.25,1.66),P ＜ 0.05],and the protein expression of the phosphorylated Tie 2 in Group M &S were decreased [0.16 (0.15,0.24) and 0.12 (0.08,0.18) vs 0.22 (0.19,0.28),P ＜ 0.05].No significant difference of Ang-1 and Tie2 expression was observed between Group L and control [5.42 (4.72,5.95),1.54 (1.43,1.66) and0.23(0.19,0.33),P=0.674,0.867 and 0.674].Conelusion With the severity of PAH,the number and function of circulating EPCs decreased,as consistent with Ang-1 and Tie2 expression changes,suggesting that function decrease of EPCs in patients with PAH may be associated with the decrease of Ang-1/Tie2 expression.

Effects of Morroniside on Expression of Angiopoietin-1 and Tie-2 in Rats after Focal Cerebral Ischemia-reperfusion / 中国康复理论与实践

Objective To explore the effects of morroniside on the expression of Angiopoietin-1 (Ang-1) and Tie-2 in a rat after focal ce-rebral ischemia-reperfusion. Methods 20 male Sprague-Dawley rats were randomly divided into sham group (n=4), ischemia group (n=4), and morroniside groups (low, medium and high dosage groups, n=4). The middle cerebral artery were occluded for 30 min, and re-perfused. Morroniside was administered intragastrically once a day at dose of 30 mg/kg, 90 mg/kg and 270 mg/kg after operation. The expression of Ang-1 and Tie-2 in the ischemic ipsilateral cortex were detected with Western blotting analysis 7 days after operation. Results The expres-sion of Ang-1 and Tie-2 increased in the ischemia group compared with the sham group (P<0.01), and both of them further increased in the morroniside groups of high dosage compared with the ischemia group (P<0.01), and the expression of Tie-2 also increased in the morroni-side groups of medium dosage (P<0.001). Conclusion Morroniside could increase the expression of Ang-1 and Tie-2 in the ischemic ipsilat-eral cortex after ischemia-reperfusion in rats, suggesting promoting the angiogenesis after ischemia.

Effects of Morroniside on Expression of Angiopoietin-1 and Tie-2 in Rats after Focal Cerebral Ischemia-reperfusion / 中国康复理论与实践

@#Objective To explore the effects of morroniside on the expression of Angiopoietin-1 (Ang-1) and Tie-2 in a rat after focal cerebral ischemia-reperfusion. Methods 20 male Sprague-Dawley rats were randomly divided into sham group (n=4), ischemia group (n=4), and morroniside groups (low, medium and high dosage groups, n=4). The middle cerebral artery were occluded for 30 min, and re-perfused. Morroniside was administered intragastrically once a day at dose of 30 mg/kg, 90 mg/kg and 270 mg/kg after operation. The expression of Ang-1 and Tie-2 in the ischemic ipsilateral cortex were detected with Western blotting analysis 7 days after operation. Results The expression of Ang-1 and Tie-2 increased in the ischemia group compared with the sham group (P<0.01), and both of them further increased in the morroniside groups of high dosage compared with the ischemia group (P<0.01), and the expression of Tie-2 also increased in the morroniside groups of medium dosage (P<0.001). Conclusion Morroniside could increase the expression of Ang-1 and Tie-2 in the ischemic ipsilateral cortex after ischemia-reperfusion in rats, suggesting promoting the angiogenesis after ischemia.

COMP-Ang1 Potentiates EPC Treatment of Ischemic Brain Injury by Enhancing Angiogenesis Through Activating AKT-mTOR Pathway and Promoting Vascular Migration Through Activating Tie2-FAK Pathway

Successful recovery from brain ischemia is limited due to poor vascularization surrounding the ischemic zone. Cell therapy with strong angiogenic factors could be an effective strategy to rescue the ischemic brain. We investigated whether cartilage oligomeric matrix protein (COMP)-Ang1, a soluble, stable and potent Ang1 variant, enhances the angiogenesis of human cord blood derived endothelial progenitor cells (hCB-EPCs) for rescuing brain from ischemic injury. COMP-Ang1 markedly improved the tube formation of capillaries by EPCs and incorporation of EPCs into tube formation with human umbilical vein endothelial cells (HUVECs) upon incubation on matrigel in vitro. COMP-Ang1 stimulated the migration of EPCs more than HUVECs in a scratch wound migration assay. The transplanted EPCs and COMP-Ang1 were incorporated into the blood vessels and decreased the infarct volume in the rat ischemic brain. Molecular studies revealed that COMP-Ang1 induced an interaction between Tie2 and FAK, but AKT was separated from the Tie2-FAK-AKT complex in the EPC plasma membrane. Tie2-FAK increased pp38, pSAPK/JNK, and pERK-mediated MAPK activation and interacted with integrins alphanubeta3, alpha4, beta1, finally leading to migration of EPCs. AKT recruited mTOR, SDF-1, and HIF-1alpha to induce angiogenesis. Taken together, it is concluded that COMP-Ang1 potentiates the angiogenesis of EPCs and enhances the vascular morphogenesis indicating that combination of EPCs with COMP-Ang1 may be a potentially effective regimen for ischemic brain injury salvage therapy.

Stimulated mast cells promote maturation of myocardial microvascular endothelial cell neovessels by modulating the angiopoietin-Tie-2 signaling pathway

Angiopoietin (Ang)-1 and Ang-2 interact in angiogenesis to activate the Tie-2 receptor, which may be involved in new vessel maturation and regression. Mast cells (MCs) are also involved in formation of new blood vessels and angiogenesis. The present study was designed to test whether MCs can mediate angiogenesis in myocardial microvascular endothelial cells (MMVECs). Using a rat MMVEC and MC co-culture system, we observed that Ang-1 protein levels were very low even though its mRNA levels were increased by MCs. Interestingly, MCs were able to enhance migration, proliferation, and capillary-like tube formation, which were associated with suppressed Ang-2 protein expression, but not Tie-2 expression levels. These MCs induced effects that could be reversed by either tryptase inhibitor [N-tosyl-L-lysine chloromethyl ketone (TLCK)] or chymase inhibitor (N-tosyl-L-phenylalanyl chloromethyl ketone), with TLCK showing greater effects. In conclusion, our data indicated that MCs can interrupt neovessel maturation via suppression of the Ang-2/Tie-2 signaling pathway.

Tie2 expressing monocytes in cancer research / 国际肿瘤学杂志

Tie2 expressing monocytes (TEMs) only present in human circulating blood and tumor organs,and have an important role in tumor angiogenesis and progression.TEMs are effectively recruited to tumors by angiopoietin 2 (Ang2) and hypoxia and then differentiate into macrophages,which promote the angiogenesis in experimental tumor models by providing paracrine support to nascent blood vessels.Studies show that TEMs are up-regulated in hepatocellular carcinoma,colorectal cancer,breast cancer,malignant glioma and other human cancers,which suggests that TEMs are conducive to diagnosis and prognosis of tumors.With the further research,TEMs are applied to deliver drugs which can obtain significant anti-tumor responses and inhibit metastasis with the ability of tumor-homing.Meanwhile,TEMs may also be a potential target for the anticancer drugs.However,the present researches indicate that the effects of TEMs in tumor microvessel density,clinical stage and prognosis are still questionable.Current works that aim at describing and predicting the concrete function of TEMs have attracted significant attention from researchers.

Effects of total saponin of Rhizoma Dioscreae Nipponicae on VEGF, Ang-2 and receptor Tie-2 in synovial tissue of CIA rats / 中国药学杂志

OBJECTIVE: To study the effects of total saponin of Rhizoma Dioscreae Nipponicae (TSRDN) on the expression of vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2) and receptor Tie-2 in synovial tissue of collagen-induced arthritis (CIA) rats, and to investigate the antiangiogenesis mechanism of TSRDN in treating rheumatoid arthritis. METHODS: After the CIA rat model was successfully established, the rats were randomly divided into 5 groups: normal control group, CIA model group, TSRDN group, tripterygium group, and diosgenin group. Real-time PCR was used to detect VEGF mRNA expression in synovial tissue of CIA rats, and immunohistochemical staining was used to observe angiopoietin-2 and receptor Tie-2. RESULTS: VEGF mRNA, Ang-2 and Tie-2 expressions in synovial tissue of CIA rats were obviously higher than normal control group (P < 0.01). After treatment with TSRDN, tripterygium, and diosgenin, the expressions of VEGF mRNA and Ang-2 were obviously lower than those in CIA model group (P < 0.01). But Tie-2 expression showed decreasing trend, and there was no obvious differences between each treatment group. VEGF mRNA expression in TSRDN group was much lower than that in tripterygium group and diosgenin group. CONCLUSION: TSRDN can inhibit angiogenesis in synovial tissue by down regulating expressions of VEGF, Ang-2 and receptor Tie-2.

Effect of cerebral ischemic preconditioning on the expressions of angiopoietin-1 and its receptor Tie-2 mRNA in cerebral ischemia in rats / 国际脑血管病杂志

Objective To investigate the effect of cerebral ischemic preconditioning (IP) on the expressions of angiopoietin-1 (Ang-1) and its receptor Tie-2 mRNA in cerebral ischemia in rats.Methods Ninety-nine Wistar rats were randomly assigned to three groups:sham operation (n =9),non-ischemic preconditioning (NIP) (n =45),and IP (n =45).The latter two groups were redivided into 5 subgroups:ischemia-reperfusion 1,3,7,14,and 21 days (n =9 in each group).A model of transient middle cerebral artery occlusion (MCAO) was induced by the intraluminal suture method for focal IP (ischemia for 10 minutes and restoring perfusion).Infarct volume was determined by 2,3,5-triphenyltetrazolium staining.The expression levels of Ang-1/Tie-2 mRNA were detected by in situ hybridization.Results The infarct volumes in the 1 -,3-,and 7-day subgroups of the IP group were significantly smaller than those in the relative subgroups of the NIP group (all P＜ 0.05).The expression of Ang-1 mRNA in the 3- and 7-day subgroups of the IP group and the expression of Tie-2 mRNA in the 1-,3-,and 7-day subgroups of the NIP group were upregulated significantly (all P ＜ 0.05).The infarct volume in the 3-day subgroup of the IP group was reduced most significantly (P ＜ 0.05).The expression of Ang-1 mRNA in the 7-day subgroup was upregulated significantly,and the peak expression of its receptor Tie-2 mRNA appeared at day 3 after IP and continued to day 7.Pearson correlation analysis showed that the expression levels of Ang-1/Tie-2 mRNA were significantly negatively correlated with infarct volume (P ＜0.01).Conclusions The expression of Ang-1/Tie-2 mRNA in the IP group was upregulated within the time window of ischemic tolerance (1 - 7 days after preconditioning),in which Ang-1 may mainly act on the later stage of the cerebral ischemic tolerance.

Association of angiopoietins and soluble angiopoietin receptor Tie-2 with diabetic retinopathy in patients with type 2 diabetes / 中华内分泌代谢杂志

Angiopoietin-2 levels were 5. 80 ( 3. 83-8. 00 ) , 4. 42 ( 2. 56-5. 55 ) , and 2. 75 ( l. 40-4. 64 )ng/ml in type 2 diabetic patients with proliferative retinopathy, patients with non-proliferative retinopathy, and patients without retinopathy, respectively. Statistical significances existed between any two groups (all P ＜0. 01 ). Angiopoietin-1 level in patients with non-proliferative retinopathy was higher than that in patients without retinopathy [10. 57 ( 8. 99-12. 05 ) vs 9. 21 (7. 71-11.2 ) ng/ml, P＜0. 05]. No difference in receptor Tie-2 was found among the 3 groups (P＞0. 05 ). The results suggested that serum angiopoietin-2 level might be associated with the severity of retinopathy in type 2 diabetic patients.

Effect of soluble Tie2 fusion protein on peritoneal angiogenesis in uremic peritoneal dialysis rats / 中华肾脏病杂志

Objective To investigate the effect of soluble Tie2 fusion protein(sTie2/Fc)on the angiogenesis of peritoneal vessels in uremic peritoneal dialysis (PD) rats.Methods Rats were randomly divided into 6 groups:normal rats as control group (group1),rats with sham operation (group2),uremic rats without PD (group3),uremic rats dialyzed with 4:25％ PD solution (group4),uremic rats dialyzed with 4.25％ PD solution and treated by subcutaneous injection of 2.5 μg/kg sTie2/Fc (group5),uremic rats dialyzed with 4.25％ PD solution and treated by subcutaneous injection of 5.0 μg/kg sTie2/Fc (group6).sTie2/Fc was given every other day during peritoneal dialysis period,total 14 doses.After regular PD for 28 days,RT-PCR and tissue immunohistochemical staining were used to detect the mRNA and protein expressions of Angpt-2 in peritoneal tissues in each group of rats.Microvessel density (MVD) of peritoneum was detected and quantified with immunohistochemical staining by using anti-CD34 antibody.Results The expression of Angpt-2 mRNA and protein was found in each group.There was no significant difference of.Angpt-2 expression both in mRNA and protein level between group1 and group2.Compared with group1,the mRNA and protein expression of Angpt-2 were significantly increased in group3 and group4 (all P＜0.05).Compared with group3,the mRNA and protein expression of Angpt-2 were significantly increased in group4 (all P＜0.05).Compared with group 4,the mRNA and protein expression of Angpt-2 were significantly decreased in group5 and group6 (all P＜0.05).Compared with group5,the mRNA and protein expression of Angpt-2 were significantly decreased in group6 (all P＜0.05).Only few new microvessel was found in group1 and group2.Compared with group1,MVD was significantly up-regulated in group3 and group4 (all P＜0.05).Compared with group4,MVD was significantly down-regulated in group5 and group6 (all P＜0.05).Conclusions Peritoneum neoangiogensis can be effectively inhibited by sTie2/Fc in uremic rat treated with PD.Blocking of signal transduction may be involved in the mechanism of sTie2/Fc inhibiting peritoneal angiogenesis.