促血管生成素及其受体的异常表达与胃癌血管生成的关系

Objective： To explore angiopoietins （Ang-1, Ang-2）/Tie-2 expression and angiogenesis in stomach carcinomas. Methods： RT-PCR and immunohistochemistry were used to detect angiopoietins/Tie- 2 mRNA and protein expression in stomach carcinomas and their adjacent normal mucosa. Microvessel density （MVD） was counted according to CD34 immunohistochemical staining. Results： There was positive expression of Angiopoietins/Tie-2 mRNA and protein in stomach carcinomas and their paired adjacent normal mucosa. It was found that correlation between Ang-1 protein, Tie-2 mRNA expression and MVD was negative （F=-0.440, F=-0.267; P〈0.05）, while the correlation between Ang-2 mRNA and its protein, Ang-2/Ang-1 protein ratio and MVD was positive （F=0.319, F=-729, F=739; P〈0.05）. Moreover, MVD in groups with Ang-2 mRNAT/N ratio over 1.2 （the ratio of Ang-2 mRNA in stomach carcinoma to its adjacent normal mucosa） was higher than those with the ratio under 1.2. Conclusion： It was suggested that Ang-1 and Ang-2 antagonizes in the angiogenesis and the anglogenesis in tumor ultimately depended on Ang-2/Ang-1 ratio, once the expression of Ang-2 is higher than Ang-1 in some degree, the angiogenesis in tumors was promoted, otherwise oppositely. In other words, Ang-2 plays dominant role in the action of angiogenesis in tumors.     

Not just angiogenesis--wider roles for the angiopoietins

Since the discovery of the angiopoietins, much interest has been focused on their biological actions and their potential use as therapeutic targets. It is generally accepted that the angiopoietins play an important role in angiogenesis and hence are described as angiogenic factors. However, it is becoming increasingly clear that this is not their only role and it is likely that the angiopoietins have important roles in a wider range of biological and pathological functions.     

Serum concentrations of angiogenic cytokines in Waldenstrom macroglobulinaemia: the ration of angiopoietin-1 to angiopoietin-2 and angiogenin correlate with disease severity

Angiogenesis represents an essential step of disease progression in several haematological malignancies. Microvessel density is increased in 30% of patients with Waldenstrom macroglobulinaemia (WM), but there is very limited information regarding the role of angiogenic cytokines in this disease. Serum levels of vascular endothelial growth factor (VEGF), VEGF-A, angiogenin, angiopoietin (Ang)-1 and -2, and basic fibroblast growth factor (bFGF) were evaluated in 56 WM patients at different disease phases (24 untreated, 20 relapsed/refractory and 12 patients at remission) and 11 patients with immunoglobulin M type monoclonal gammopathy of undetermined significance (IgM-MGUS). All patients had increased levels of angiogenin, VEGF, VEGF-A, and bFGF compared with controls. The Ang-1/Ang-2 ratio was reduced in WM but not in IgM-MGUS patients. Angiogenin levels correlated with disease status: when compared with healthy subjects, patients with IgM-MGUS and untreated WM patients had increased angiogenin serum levels, which were higher in untreated WM patients than in MGUS. WM patients at remission had lower angiogenin serum levels compared with untreated patients, but these levels were increased again in active disease post-therapy. Angiogenin also correlated with albumin levels, while VEGF-A correlated with beta(2)-microglobulin (beta2M). Ang-1/Ang-2 ratio showed a strong, negative correlation with beta2M, and positive correlation with albumin, haemoglobin and lymphadenopathy. Our results indicate a potential use of angiogenin levels for follow-up in WM and angiogenic molecules as targets for the development of novel anti-WM agents.     

Identification and characterisation of chicken cDNAs encoding the endothelial cell-specific receptor tyrosine kinase Tie2 and its ligands, the angiopoietins

The angiopoietins represent a recently discovered family of angiogenic factors that recognise and specifically bind to the endothelial cell-specific Tie2 receptor tyrosine kinase. The specific biological functions of the angiopoietins have not yet been elucidated, although transgenic technology has shown the critical roles that these proteins have in vascularisation. The chicken vasculature, and more particularly the chorioallantoic membrane, is an important tool in the study of angiogenesis and has been previously used to study the functions of angiogenic factors such as vascular endothelial growth factor. We have undertaken the identification of the chicken orthologs of the angiopoietins and the Tie2 receptor. cDNA clones that encompass the full coding sequence of chicken Tie2 show features typical of this family of receptor tyrosine kinases. Chicken angiopoietin-1 and angiopoietin-2 show a high degree of homology to their human counterparts, 91% and 87% respectively, a reflection of the critical role of this signalling pathway. This revised version was published online in June 2006 with corrections to the Cover Date.     

Functional and molecular mapping of uncoupling between vascular permeability and loss of vascular maturation in ovarian carcinoma xenografts: the role of stroma cells in tumor angiogenesis

Maintaining homogeneous perfusion in tissues undergoing remodeling and vascular expansion requires tight orchestration of the signals leading to endothelial sprouting and subsequent recruitment of perivascular contractile cells and vascular maturation. This regulation, however, is frequently disrupted in tumors. We previously demonstrated the role of tumor-associated myofibroblasts in vascularization and exit from dormancy of human ovarian carcinoma xenografts in nude mice. The aim of this work was to determine the contribution of stroma- and tumor cell-derived angiogenic growth factors to the heterogeneity of vascular permeability and maturation in MLS human ovarian carcinoma tumors. We show by RT-PCR and by in situ hybridization that VEGF was expressed by the tumor cells, while angiopoietin-1 and -2 were expressed only by the infiltrating host stroma cells. Vascular maturation was detected in vivo by vasoreactivity to hypercapnia, measured by BOLD contrast MRI and validated by immunostaining of histologic sections to alpha-smooth muscle actin. Vascular permeability was measured in vivo by dynamic contrast-enhanced MRI using albumin-based contrast material and validated in histologic sections by fluorescent staining of the biotinylated contrast material. MRI as well as histologic correlation maps between vascular maturation and vascular permeability revealed a wide range of vascular phenotypes, in which the distribution of vascular maturation and vasoreactivity did not overlap spatially with reduced permeability. The large heterogeneity in the degree of vascular maturation and permeability is consistent with the differential expression pattern of VEGF and angiopoietins during tumor angiogenesis.     

促血管生成素表达与人脑胶质瘤血管生成的关系研究

目的:研究促血管生成素(angiopoie-tins,Angs)蛋白表达水平与血管内皮生长因子(vascular endothelial growth factar,VEGF)和肿瘤内微血管密度(microvascular density,MVD)的关系,探讨其在人脑胶质瘤血管生成中的作用。方法:采用免疫组化方法检测42例人脑胶质瘤组织中Ang-1、Ang-2和VEGF的蛋白表达水平,并以抗CD34单克隆抗体显示血管内皮细胞,根据CD34阳性的血管计数来判定MVD。结果:42例人脑胶质瘤中,Ang-1+肿瘤的MVD比Ang-1-肿瘤高,但两者差异无统计学意义,P=0·156;Ang-2-和Ang-2+平均MVD分别是27·67和49·63,Ang-2+肿瘤MVD显著高于Ang-2-肿瘤,P=0·000。VEGF阳性表达时,Ang-2+肿瘤平均MVD显著高于Ang-2-肿瘤,分别为56·00和36·75,P=0·001;而VEGF阴性组中,Ang-2+肿瘤平均MVD与Ang-2-肿瘤几乎相等,分别为53·17和47·36,P=0·109。随胶质瘤恶性程度增加,Ang-1和Ang-2阳性表达率均升高,但Ang-2升高更明显,不同级别间Ang-2表达水平差异有统计学意义。结论:Ang-2高表达与人脑胶质瘤血管新生密切相关,Ang-2可以作为评价胶质瘤血管生成及恶性程度的一个重要指标。VEGF存在时,Ang-2过表达可促使肿瘤血管生成。肿瘤防治杂志,2005,12(19):1472-1475     

Pulmonary vascular inflammation: effect of TLR signalling on angiopoietin/TIE regulation

Increased pulmonary vascular resistance is a critical complication in sepsis. Toll‐like receptor (TLR) as well as angiopoietin (ANG) signalling both contribute to the emergence of pulmonary arterial hypertension. We hypothesized that TLR stimulation by bacterial ligands directly affects expression and secretion of ligands and receptors of the angiopoietin/TIE axis. Microvascular endothelial (HPMEC) and smooth muscle cells (SMC) of pulmonary origin were incubated with thrombin and with ligands for TLR2, ‐4, ‐5, and ‐9. Expression and secretion of ANG1, ‐2, TIE2 and IL‐8 were determined using quantitative real‐time PCR and ELISA. TLR stimulation had no impact either on the expression of ANG2 and TIE2 in HPMEC or on that of ANG1 in SMC. However, overall levels of both released ANG1 and ‐2 were halved upon stimulation with the TLR9 ligand CpG, and ANG2 release was significantly enhanced by TLR4 activation when initially provoked by sequentially performed stimulation. Furthermore, enhanced ANG2 activity increased endothelial permeability, as demonstrated in an in vitro transwell assay. We conclude that sole TLR stimulation by bacterial ligands plays no significant role for altered expression and secretion of ANG1, ‐2 and TIE2 in human pulmonary vascular cells. The interplay between various stimuli is required to induce imbalances between ANG1 and ‐2.     

促血管生成素表达与人脑胶质瘤血管生成的关系研究

目的：研究促血管生成素（angiopoietins,Angs）蛋白表达水平与血管内皮生长因子（vascular endotheljal growth factar,VEGF）和肿瘤内微血管密度（microvascular density,MVD）的关系,探讨其在人脑胶质瘤血管生成中的作用.方法：采用免疫组化方法检测42例人脑胶质瘤组织中Ang-1、Ang 2和VEGF的蛋白表达水平,并以抗CD34单克隆抗体显示血管内皮细胞,根据CD34阳性的血管计数来判定MVD.结果：42例人脑胶质瘤中,Ang 1＋肿瘤的MVD比Ang-1-肿瘤高,但两者差异无统计学意义,P=0.156;Ang-2和Ang-2^＋平均MVD分别是27.67和49.63,Ang-2^＋肿瘤MVD显著高于Ang-2肿瘤,P=0.000.VEGF阳性表达时,Ang-2^＋肿瘤平均MVD显著高于Ang 2肿瘤,分别为56.00和36.75,P=0.001;而VEGF阴性组中,Ang-2^＋肿瘤平均MVD与Ang-2^-肿瘤几乎相等,分别为53.17和47.36,P=0.109.随胶质瘤恶性程度增加,Ang-1和Ang-2阳性表达率均升高,但Ang-2升高更明显,不同级别间Ang-2表达水平差异有统计学意义.结论：Ang-2高表达与人脑胶质瘤血管新生密切相关,Ang-2可以作为评价胶质瘤血管生成及恶性程度的一个重要指标.VEGF存在时,Ang-2过表达可促使肿瘤血管生成.     

血管生成素与脑缺血

血管生成素(angiopoietin,Ang)是一族特异性作用于血管内皮细胞的生长因子,Tie-2为其内皮特异性共同受体,Ang1能保持血管内皮的稳定性,促使血管成熟;Ang2能拮抗Ang1,破坏血管的稳态,与内皮细胞的增殖有关。Ang及其受体在缺血脑组织中的特异表达与脑缺血半暗带血管重建、侧支循环的形成和血脑屏障的完整性密切相关,有望成为缺血性卒中新的治疗靶点。