血管生成素及其受体在腹膜透析腹膜组织中的表达

目的 分析并研究尿毒症腹膜透析大鼠腹膜血管生成素(Ang)及其受体(Tie)的表达情况及影响因素.方法 SD雄性大鼠5/6肾切除术建立尿毒症模型,成模后腹腔内植入腹透管,随机分为尿毒症组(NS组)及腹透组(PD组).尿毒症组每日给予20 ml生理盐水腹腔灌注,腹透组每日给予20 ml 4.25%百特腹透液腹腔灌注,持续6周.对照组(C组)行假手术且不予液体灌注.实验结束取大鼠腹膜组织,观察腹膜血管新生情况;行免疫组化及RT-PCR检测腹膜组织血管生成素及其受体的表达变化.结果 实验表明PD组相对其他两组新生血管数明显增多,NS组新生血管数较C组为多(P均<0.05).免疫组化显示Ang2及其Tie2阳性细胞数PD组相对于C组和NS组明显增加,NS组较C组亦有增加(P均<0.05).RT-PCR显示PD组Ang2 mRNA和Tie2 mRNA表达较NS组和C组明显上调,而NS组高于C组(P均<0.05).结论 尿毒症本身及腹膜透析液均会上调腹膜的血管生成素及其受体表达,且与血管新生密切相关.     

血管生成素及其受体与肿瘤的血管生成

血管生成素 (Ang)家族是唯一含受体激动剂及抑制剂的促血管生成因子 ,编码四种结构相似的蛋白质 ,包括Ang 1,Ang 2 ,Ang 3和Ang 4 ,均能与内皮细胞上的酪氨酸激酶受体Tie 2结合 ,参与生理性及病理性的血管生成。Ang 1激活Tie 2 ,促进血管生成 ,维持血管稳定 ;Ang 2的作用呈VEGF依赖性 ,VEGF存在时 ,可促进血管出芽 ,VEGF缺乏时 ,则促进血管退化。Ang家族在不同的肿瘤中表达水平及分布形式不一。应用sTie 2或以Ang家族为靶标可抑制肿瘤性血管生成 ,对肿瘤的治疗有潜在的应用前景。     

膀胱移行细胞癌中促红细胞生成素及其受体的表达

目的探讨促红细胞生成素（EPO）及其受体（EPOR）在膀胱移行细胞癌（TCC）组织中的表达,并探讨其临床意义。方法应用免疫组织化学方法、RT-PCR方法检测70例膀胱TCC组织、15例癌旁组织、10例正常膀胱组织中EPO和EPOR的蛋白和 mRNA的表达。结果70例膀胱TCC组织有44例（62.9%）EPO蛋白阳性表达,有29例（41.4%）EPOR蛋白阳性表达;15例膀胱TCC癌旁组织及10例正常膀胱组织均未见EPO、EPOR蛋白的表达。EPO蛋白表达强度与膀胱TCC的组织学分级相关（rs=0.329,P〈0.05）,而与临床分期则无明显的相关性。膀胱癌组织中EPO与EPOR表达具有相关性（rs=0.346,P〈0.01）。RT-PCR检测发现膀胱移行细胞癌组织中EPO及其受体 mRNA的表达明显高于正常膀胱组织、癌旁组织中EPO及其受体 mRNA的表达（P〈0.01）。结论EPO、EPOR在膀胱TCC组织中过表达,提示EPO、EPOR在膀胱TCC的发生、发展过程中可能起重要作用;EPO蛋白表达强度与膀胱TCC的组织学分级有明显相关性,可能成为膀胱TCC不良预后的指标之一。     

促甲状腺激素与视网膜新生血管形成

视网膜新生血管形成主要见于糖尿病视网膜病变(DR)、早产儿视网膜病(ROP)及视网膜中央静脉阻塞(CRVO),是视网膜病变的主要致盲原因。有研究表明高水平促甲状腺激素(TSH)可能促进了视网膜新生血管形成,其作用机制可能与TSH与其受体结合后激活了血管内皮生长因子(VEGF)和环磷酸腺苷-雷帕霉素靶蛋白(cAMP-mTOR)信号通路而使血管生成增加有关。     

Epo-受体产品抑制促红细胞生成素诱导高血压

明尼苏达大学的Jong Y．Lee博士及其同事在8月的《高血压》（Hypertension，2007；50：439-445．）上报道，基因工程产品促红细胞生成素结合蛋白（Epo-bp）和抗Epo-bp抗体可以预防促红细胞生成素诱导的高血压，不影响红细胞压积。     

血管生成素的特点及其对血管生成的调节作用

器官和组织的血管生成包括两个过程 :血管形成 (ｖａｓｃｕｌｏｇｅｎｅｓｉｓ)和血管新生 (ａｎｇｉｏｇｅｎｅｓｉｓ)。目前研究表明有两条调节途径参与了血管生成过程 ;一条是血管内皮生长因子 (ｖａｓｃｕｌａｒｅｎｄｏｔｈｅｌｉａｌｇｒｏｗｔｈｆａｃ ｔｏｒ,ＶＥＧＦ)及其受体(ｆｌｔ-1等 )调节通路 ,另一条是血管生成素 (ａｎｇｉｏｐｏｉｅｔｉｎ ,Ａｎｇ)及其受体 (Ｔｉｅ)调节通路。这两条途径协同作用 ,共同促进机体血管形成。近年来对血管生成素及其Ｔｉｅ受体调节通路的研究越来越受到人们重视。1　血管生成素 (ａｎｇｉｏ…     

促红细胞生成素肝细胞激酶受体与ephrin配体及其信号转导在肿瘤中的研究进展

促红细胞生成素肝细胞激酶(erythropoietin producing hepatocyte kinase,Eph)受体及其膜结合配体ephrin是最大的受体酪氨酸激酶(receptor tyrosine kinases,RTKs)家族,其不仅调节生物体的多种生理功能,而且参与多种疾病的发生发展过程.近年来,已有越来越多的证据表明肿瘤的发生发展与Eph家族成员异常表达密切相关.     

雌激素受体与数种血管形成因子在血管瘤和血管畸形中的表达

目的:探讨雌激素受体与数种血管形成因子在血管瘤和血管畸形病理发生中的作用。方法:对35例手术切除的血管瘤及血管畸形标本及5例正常皮肤标本,采用免疫组织化学方法检测雌激素受体以及血管形成有关的血管内皮细胞生长因子、基质金属蛋白酶和组织蛋白酶D。结果:在血管瘤增生期,ER、VEGF、MMP-2及组织蛋白酶D均有较高表达;在血管瘤退化期,仅ER和组织蛋白酶D有较高表达;在血管畸形和正常皮肤对照中,ER、VEGF和MMP-2表达极弱,组织蛋白酶D有少许表达。结论:雌激素与多种血管形成因子可通过不同途径对血管瘤的病理发生过程发挥作用,对血管畸形则无作用。     

红细胞生成素受体功能域的研究及其意义

红细胞生成素受体是细胞因子受体超家族成员之一。它在红细胞生成素诱导的红系祖细胞的存活、增殖、分化的过程中起着重要的调节作用。本文概述了红细胞生成素受体3个功能域的结构、主要功能及其在医药研究中的重要意义。     

黄体生成素及其受体在大鼠肝脏的定位

目的观察黄体生成素(LH)及其受体(LHR)在大鼠肝脏的定位分布,为研究LH是否参与肝代谢功能的调节提供形态学依据。方法应用免疫荧光组织化学双标染色技术,在激光共聚焦扫描显微镜下观察染色结果。结果大鼠肝细胞既呈LH阳性又有LHR阳性,LH和LHR免疫反应阳性物质均分布在大鼠肝细胞的细胞质,细胞核为阴性。不同部位的肝细胞LH及其受体免疫反应强度存在差别。结论 LH及其受体存在于大鼠肝脏细胞,可能对肝脏的功能起调节作用。     

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.     

蛋白多糖在肿瘤血管生成中的作用

血管生成是肿瘤进展中的一个重要环节。蛋白多糖(proteoglycans,PGs)由核心蛋白和不同的糖胺聚糖(glycosaminoglycans,GAGs)侧链构成,属于细胞外基质(extracellular matrix,ECM)的非胶原重要成分。研究显示PGs与肿瘤的发生发展密切相关,可参与肿瘤血管生成过程。由于其侧链的不同,功能上也会出现差异,表现出促进或抑制肿瘤血管生成的作用。本文就PGs在肿瘤血管生成中的作用研究现状作一综述。     

Angiogenetic axis angiopoietins/Tie2 and VEGF in familial breast cancer

Angiogenesis leads to the formation of blood vessels from pre-existing ones, allowing tumor growth. Vascular endothelial growth factor (VEGF) and Angiopoietins (Ang-1, Ang-2) have a pivotal role in tumor angiogenesis but few data regarding their role in hereditary breast cancer are available. The aim of the present study was to analyze Ang-1, Ang-2, tyrosine-protein kinase receptor Tie2 and VEGF expression and their correlation in a cohort of familial and sporadic breast cancers in order to verify whether the presence of germline mutations in BRCA may have a role in tumor microenvironment regulation. Tumor samples from a cohort of 41 patients with a first diagnosis and a family history of breast cancer and 19 patients with sporadic breast cancers were enrolled. The expression of Tie2, Ang-1, Ang-2 and VEGF were analyzed by quantitative real-time PCR. Patients harboring BRCA mutations had higher levels of Ang-1 (P=0.05), Ang-2 (P=0.02) and VEGF (P=0.04) mRNA compared with those without BRCA mutations (BRCAX). The same was observed in triple-negative breast cancer (TNBC). Moreover, a positive correlation between Ang-2 and VEGF was found in both the familial breast cancer group (BRCA carriers: r=0.83; P<0.0001 and BRCAX: r=0.58; P=0.008) and in TNBC (r=0.62; P=0.007). The higher levels of Ang-1, Ang-2 and VEGF mRNA found in BRCA carriers and TNBCs suggest that they could be attractive angiogenic therapeutic targets in these breast cancers.     

The role of angiopoietins during angiogenesis in gliomas

The formation of new blood vessels plays an important role in human disease development and progression. For instance, it is well established that the growth of most cancers critically depends on the supply of nutrition and oxygen by newly recruited blood vessels. Similarly, malignant gliomas, the most common primary brain tumors occurring in humans are highly dependent on angiogenesis. In recent years, there has been tremendous effort to uncover the molecular mechanisms that drive blood vessel growth in adult tissues, especially during cancer progression. Vascular endothelial growth factor (VEGF) and other morphogens, such as angiopoietins and ephrins have been shown to be critically involved in the formation of new blood vessels during both developmental and pathological angiogenesis as evidenced by genetic studies in mice. In this review, we focus on angiopoietins, a family of growth factor ligands binding to Tie tyrosine kinase receptors with emphasis on their functional consequences during the growth and progression of experimental tumors and malignant human gliomas.     

Erythropoietin/erythropoietin receptor system is involved in angiogenesis in human neuroblastoma

AIMS: Previous studies have shown that increased vascularity is associated with tumour progression in human neuroblastoma (NB). The involvement of erythropoietin (Epo) in tumour angiogenesis has also been reported. The aim of this study was to correlate microvascular density and Epo/Epo-receptor (EpoR) expression in endothelial and tumour cells to the clinical stage of NB. METHODS AND RESULTS: Specimens of NB obtained from 20 patients were investigated immunohistochemically by using anti-CD31, anti-Epo and anti-EpoR antibodies. The extent of angiogenesis was found to be up-regulated in advanced disease. In keeping with this observation, Epo/EpoR expression in tumour and endothelial cells, respectively, was also highly correlated with the extent of angiogenesis and higher clinical stage. CONCLUSIONS: The correlation of Epo/EpoR expression with angiogenesis and tumour progression suggests the presence of a loop in the Epo-EpoR system. Epo is secreted by tumour cells and affects vascular endothelial cells via its receptor, promoting tumour angiogenesis in a paracrine manner. Data suggest that Epo represents an important mediator in NB angiogenesis. Understanding the mechanisms of NB angiogenesis provides the basis for a rational approach to the development of antiangiogenic therapy in patients affected by NB.     

Erythropoietin/erythropoietin-receptor system is involved in angiogenesis in human hepatocellular carcinoma

AIMS: To correlate microvascular density and erythropoietin (Epo)/Epo-receptor (EpoR) expression in endothelial and tumour cells with histopathological type in hepatocellular carcinoma (HCC). Methods AND RESULTS: Specimens of primary HCC obtained from 50 patients who had undergone curative hepatectomy were investigated immunohistochemically by using anti-CD31, anti-Epo and anti-EpoR antibodies. Poorly differentiated HCC had a higher degree of vascularization than other stages and Epo/EpoR expression in both tumour and endothelial cells increased in parallel with grade of malignancy and was highly correlated with the extent of angiogenesis. CONCLUSIONS: Epo/EpoR levels correlate with angiogenesis and progression of patients with HCC and these findings suggest the presence of a loop in the Epo/EpoR system, i.e. Epo is secreted by hepatic tumour cells and it affects vascular endothelial cells via its receptors and promotes angiogenesis in a paracrine manner. It is thus suggested that Epo is an important factor in hepatic tumour angiogenesis. Understanding the mechanisms of HCC angiogenesis provides a basis for a rational approach to the development of antiangiogenic therapy in patients with hepatic cancer.     

Differential expression of angiopoietins 1 and 2 and their receptor Tie-2 in human endometrium

Angiogenesis, the growth of new capillaries from pre-existing blood vessels, is a physiological process involved in both normal menstrual cycling and implantation of the embryo. So far, very little is known about the expression of angiopoietins, growth factors involved in angiogenesis, in human endometrium. Both angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are ligands for the endothelial cell-specific receptor tyrosine kinase Tie-2. In this study we determined the mRNA expression of Ang-1, Ang-2 and Tie-2 by quantitative competitive RT/(QC)-PCR (including specifically designed competitor cDNA) in biopsied human endometrium throughout the menstrual cycle. We detected the mRNA for the angiopoietins in 30 out of 32 endometrial biopsies (94%), covering early proliferative (n = 4), mid proliferative (n = 12), late proliferative (n = 3), early secretory (n = 3), mid secretory (n = 5) and late secretory (n = 3) phases. Analysis of the target/competitor ratios (QC-PCR) revealed that Ang-1 mRNA expression was significantly up-regulated (P = 0.027) during the secretory phase of the menstrual cycle. In contrast, the expression levels of both Ang-2 mRNA and Tie-2 mRNA showed only minor variations at different cycle stages. These findings were confirmed by the relative expression ratio of Ang-1 versus Ang-2 in a multiplex PCR. The expression of Ang-1, Ang-2 and Tie-2 mRNA was detected in both isolated endometrial epithelial and stromal cell fractions. Immunohistochemical localization of the proteins revealed qualitative differences in both cell type and cycle stage expression. In conclusion, the enhanced Ang-1 expression during the secretory phase might serve to stabilize the newly developed blood vessels.     

Angiopoietins in tumours: the angiogenic switch

On first view, the literature pertaining to the expression of the angiopoietins in tumours is confusing and does not readily offer a consensus pattern. Apparently conflicting publications report increased, decreased or unchanged expression levels of both angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) in a wide range of tumours. However, closer scrutiny of the literature, taking into account relative increases or decreases of each factor, reveals a consensus pattern, seen in almost all instances of expression profiling of the angiopoietins in tumours. What becomes apparent is that although absolute levels of either angiopoietin may increase or decrease, the ratio of Ang-1:Ang-2 shifts in favour of Ang-2. Given that Ang-2 is a destabilization factor, rendering vasculature in a more plastic state amenable to sprouting (under the influence of vascular endothelial growth factor, VEGF) or regression, this analysis suggests that tumours shift the angiogenic balance towards a pro-angiogenic state through altering the balance between the angiopoietins. This in turn implicates Ang-2 as a candidate for the angiogenic switch and also as an important potential therapeutic target.