血管生成素与眼部新生血管的关系

血管生成素(angiopoietin,Ang)是特异性作用于血管内皮细胞的生长因子,主要由Ang-1和Ang-2组成;Tie2(tyrosinekinasethatcontainsim-munoglubin-likeloopsandepidermalgrowthfac-tor-similardomains2)是其共同受体。Ang-1促使血管成熟,维持血管稳定。Ang-2则拮抗Ang-1的作用,始动病理性新生血管形成。在眼部新生血管形成过程中Ang/Tie2受体途径起重要作用,抑制Ang/Tie2受体途径可以抑制眼部新生血管形成。     

Expression of angiopoietin‐like protein 4 at the fracture site: Regulation by hypoxia and osteoblastic differentiation

Vascular disruption that occurs as a consequence of bone fracture, leads to hypoxia at the site of damage. Hypoxia regulates the expression of a number of genes that can modulate energy conservation, cell survival, tissue regeneration and angiogenesis. In this study we investigated the expression of Angiopoietin‐like 4, an adipocytokine that has additional roles in angiogenesis, at the fracture site. We demonstrate that Angptl4 mRNA expression increased early during fracture healing (day 3) returning close to baseline at day14. In the callus, Angptl4 mRNA was visualized in areas of condensing mesenchymal cells, callus cartilage and was especially high in mineralizing osteoblasts located in areas of new bone formation. In vitro, Angptl4 mRNA expression in osteoblasts increased under hypoxic conditions and in cells treated with the hypoxia mimetic desferrioxamine. Angptl4 levels were strongly induced at day 14 in differentiating MC3T3‐E1 osteoblastic cells. Exogenous ANGPTL4 increased expression of Runx2, Spp1, vegfa, and Alp mRNA in differentiating osteoblasts. We suggest that the distribution of Angptl4 in the callus may be driven by hypoxia and that Angptl4 may play a role in osteoblastic differentiation, and possibly angiogenesis via regulation of VEGF. Further studies could reveal a dual role for Angptl4 in angiogenesis and osteogenesis. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1364–1373, 2015.     

Gene control of tyrosine kinase TIE2 and vascular manifestations of infections

Ligands of the endothelial-enriched tunica interna endothelial cell kinase 2 (Tie2) are markedly imbalanced in severe infections associated with vascular leakage, yet regulation of the receptor itself has been understudied in this context. Here, we show that TIE2 gene expression may constitute a novel vascular barrier control mechanism in diverse infections. Tie2 expression declined rapidly in wide-ranging models of leak-associated infections, including anthrax, influenza, malaria, and sepsis. Forced Tie2 suppression sufficed to attenuate barrier function and sensitize endothelium to permeability mediators. Rapid reduction of pulmonary Tie2 in otherwise healthy animals attenuated downstream kinase signaling to the barrier effector vascular endothelial (VE)-cadherin and induced vascular leakage. Compared with wild-type littermates, mice possessing one allele of Tie2 suffered more severe vascular leakage and higher mortality in two different sepsis models. Common genetic variants that influence TIE2 expression were then sought in the HapMap3 cohort. Remarkably, each of the three strongest predicted cis-acting SNPs in HapMap3 was also associated with the risk of acute respiratory distress syndrome (ARDS) in an intensive care unit cohort of 1,614 subjects. The haplotype associated with the highest TIE2 expression conferred a 28% reduction in the risk of ARDS independent of other major clinical variables, including disease severity. In contrast, the most common haplotype was associated with both the lowest TIE2 expression and 31% higher ARDS risk. Together, the results implicate common genetic variation at the TIE2 locus as a determinant of vascular leak-related clinical outcomes from common infections, suggesting new tools to identify individuals at unusual risk for deleterious complications of infection.Among vascular-enriched receptor tyrosine kinases, Tie2 is unusual in at least two functional aspects. First, Tie2 phosphorylation is tightly controlled by the interplay of several proteins: a paralogous receptor, Tie1; a tyrosine phosphatase, vascular endothelial-protein tyrosine phosphatase (VE-PTP); and two secreted ligands, angiopoietin (Angpt)-1 and Angpt-2, the latter of which can act as an agonist, partial agonist, or antagonist depending upon context (1–6). Second, unlike classic growth factor receptors, Tie2 is heavily expressed and phosphorylated throughout the quiescent adult vasculature (7), suggesting that Tie2 signaling has one or more roles in vascular maintenance.Based largely on Angpt-1 overexpression studies, Tie2 has been implicated in vascular barrier defense (8, 9). However, adult-specific deletion of Angpt-1 does not appear to trigger vascular leakage (10). Moreover, Angpt-1 has repeatedly been ascribed functions that are independent of Tie2 (11–13). Finally, observational studies in humans suffering clinical manifestations of vascular leakage have consistently shown a marked imbalance in Tie2 ligands tilting in favor of Angpt-2 (reviewed in 14). Although decreased Tie2 activity has been inferred from these reports, the role of TIE2 gene expression has not been directly queried experimentally or in clinical settings.This question is important not only for understanding control mechanisms of the circulatory system but also to guide the development of strategies to predict, stratify, and treat patients affected by acute vascular leakage. If tonic Tie2 signaling is indeed necessary for vascular barrier maintenance, then reducing the pool of receptors could constitute a ligand-independent means to attenuate barrier-protective signaling in the endothelium. We therefore hypothesized that the level of Tie2 expression modulates the sensitivity of blood vessels, and thereby the entire organism, to noxious stimuli. Cellular, rodent, and human genetics studies were undertaken to test this concept.     

心力衰竭患者血浆CTRP3、血管生成素样蛋白2、sST2的浓度及预后价值

目的探讨心力衰竭患者血浆补体C1q肿瘤坏死因子相关蛋白3(C1q tumor necrosis factor related proteins-3,CTRP3)、血管生成素样蛋白2(angiopoietin like protein 2,angptl2)、可溶性致癌抑制因子2(soluble suppression of tumorigenicity 2,sST2)的浓度及预后价值。方法选择2014年8月到2018年2月在北京市垂杨柳医院心内科收治的心力衰竭患者122例作为心力衰竭组,并分为收缩性心力衰竭组62例和舒张性心力衰竭组60例两个亚组;对照组为非心力衰竭人群122例。采用酶联免疫吸附法检测混杂血浆CTRP3、angptl2、sST2浓度,随访调查患者的预后并进行相关性分析与预测价值分析。结果心力衰竭组的左心室射血分数(left ventricular ejection fraction,LVEF)低于对照组,左心室舒张末期内径(left ventricular end diastolic dimension,LVEDD)及血尿素、肌酐浓度高于对照组,差异有统计学意义(P<0.05)。两组总胆固醇、低密度脂蛋白胆固醇浓度比较,差异无统计学意义(P>0.05)。两亚组心功能与生化指标比较,差异无统计学意义(P>0.05)。心力衰竭组的血浆angptl2、sST2浓度高于对照组,CTRP3浓度低于对照组,差异有统计学意义(P<0.05);两亚组CTRP3、angptl2、s ST2浓度比较,差异无统计学意义(P>0.05)。随访至今,心力衰竭组患者中预后不良16例,发生率为13.1%。Pearson相关分析结果显示CTRP3、angptl2、sST2、LVEF、LVEDD、尿素、肌酐都与心力衰竭患者预后显著相关(P<0.05)。Cox回归模型分析显示CTRP3、angptl2、sST2为影响心力衰竭患者预后的主要因素(P<0.05)。结论心力衰竭患者血清CTRP3、angptl2、sST2浓度呈现异常表达情况,具有预测预后不良的价值,是心力衰竭预后评估的生物学标志物。     

A Mildly Altered Vascular Homeostasis in Early Stage of CKD

Background. A continuous increase in number of CKD patients entering ESRD is a growing public health threat, which reflects the present therapeutic failure usually initiating at the late stage of CKD. Objective. To study the mechanism of vascular repair in CKD patients associated with mildly impaired renal function, which included angiogenic factors such as VEFG, angiopoietin-1, and flt-1 (VEGFR1); and antiangiogenic factors such as angiopoietin-2 and KDR (VEGFR2). Results. A mild defect in angiogenic factor—namely, angiopoietin-1—was observed, whereas VEGF and flt-1 (VEGFR1) were within normal limit. Also, antiangiogenic factor—namely, angiopoietin-2—was mildly elevated, whereas KDR (VEGFR2) remained within normal limit. Conclusion. The mechanism of vascular repair appears to be adequately functional in the early stage of CKD. Therapeutic intervention at this stage can improve renal perfusion and restore renal function as indicated in normoalbuminuric, type 2 diabetic nephropathy. The authors encourage changing the conceptual view of treatment under common treatment at late stage of CKD to treatment at early stage of CKD under an environment favorable for renal regeneration.     

血清血管生成素1与血管生成素2比值对2型糖尿病微血管病变的诊断价值

目的 探讨血清血管生成素1(Ang-1)与血管生成素2(Ang-2)比值对2型糖尿病(T2DM)微血管病变的诊断价值。方法 选取2018年1-12月期间在山西医科大学附属第二医院(下称本院)接受治疗的T2DM患者98例,根据是否合并微血管病变将98例患者分为微血管病变组(42例)和单纯T2DM组(56例),另选取同期在本院体检的健康人群50例作为对照组。检测各组研究对象的空腹血糖(FPG)、糖化血红蛋白(HbA1c)、空腹胰岛素(FINS)、胰岛素抵抗指数(HOMA-IR)、Ang-1、Ang-2、Ang-1/Ang-2。结果 微血管病变组的体质量指数、FPG、HbA1c、HOMA-IR、Ang-2均高于单纯T2DM组和对照组,Ang-1/Ang-2低于单纯T2DM组和对照组,差异有统计学意义(P<0.05),微血管病变组的病程长于单纯T2DM组,FINS高于对照组,差异有统计学意义(P<0.05),单纯T2DM组的体质量指数、FPG、FINS、HbA1c、HOMA-IR、Ang-2均高于对照组,Ang-1/Ang-2低于对照组,差异有统计学意义(P<0.05),Ang-2与病程、HbA1c呈正相关(r分别为0.421、0.391,P<0.05),Ang-1/Ang-2与病程、HbA1c呈负相关(r分别为-0.548、-0.423,P<0.05),Ang-1、Ang-2、Ang-1/Ang-2曲线下的面积分别为0.625、0.737、0.902,约登指数分别为0.134、0.549、0.744。结论 血清Ang-2在T2DM微血管病变患者中呈高表达,而Ang-1/Ang-2则明显降低,且Ang-1/Ang-2对T2DM患者微血管病变有较高的诊断价值。     

3‐O‐Acetyloleanolic acid inhibits angiopoietin‐1‐induced angiogenesis and lymphangiogenesis via suppression of angiopoietin‐1/Tie‐2 signaling

Tumor angiogenesis and lymphangiogenesis are important processes in tumor progression and metastasis. The inhibitory effects of 3‐O‐acetyloleanolic acid (3AOA), a pentacyclic triterpenoid compound isolated from Vigna sinensis K., on tumor‐induced angiogenesis and lymphangiogenesis in vitro and in vivo were studied. Angiopoietin‐1 is an important angiogenic and lymphangiogenic factor secreted from colon carcinoma CT‐26 cells under hypoxia conditions. 3AOA inhibited proliferation, migration, and tube formation of angiopoietin‐1‐treated human umbilical vein endothelial cells (HUVEC) and human lymphatic microvascular endothelial cells (HLMEC). 3AOA reduced angiogenesis and lymphangiogenesis in angiopoietin‐1‐stimulated Matrigel plugs. Also, 3AOA inhibited tumor growth and tumor‐induced angiogenesis and lymphangiogenesis in an angiopoietin‐1‐induced CT‐26 allograft colon carcinoma animal model. 3AOA inhibited activation of the angiopoietin‐1 receptor Tie‐2 and activation of the downstream signaling factors FAK, AKT, and ERK1/2 that are involved in the angiopoietin‐1/Tie‐2‐signaling pathway. Thus, 3AOA has an inhibitory effect on angiogenesis and lymphangiogenesis induced by angiopoietin‐1 both in vitro and in vivo, and the inhibitory effect of 3AOA is probably due to suppression of angiopoietin‐1/Tie‐2 signaling in HUVEC and HLMEC.     

血管生成素及其受体Tie2在婴幼儿血管瘤表达的研究

目的研究婴幼儿血管瘤血管内皮细胞血管生成素及其受体Tie2的表达情况,初步探讨婴幼儿血管瘤生长异常的病理生理学机制,为其治疗奠定理论基础。方法以40例血管瘤患儿手术切除的血管瘤组织为研究对象,其中增生期和消退期标本各20例,另取正常皮肤组织（包茎患儿包皮环切术切除的包皮组织）20例作为正常对照。应用半定量PCR技术检测血管生成素-1（Angl）、血管生成素一2（Ang2）及其受体Tie2 mRNA表达情况;应用Western blotting技术检测Ang1、Ang2及其受体Tie2蛋白表达情况。结果Rt—PCR和Westem blotting结果均显示：在增生期和消退期瘤体中,Ang1 mRNA和蛋白的表达量明显低于正常包皮组织,P〈0．05;Ang2和Tie2 mRNA和蛋白的的表达量明显高于正常包皮组织,P〈0．05;三者的表达在增生期和消退期瘤体之间没有统计学差异,P〉0．05。结论婴幼儿血管瘤中存在Ang1、Ang2和Tie2的异常表达,可能参与了血管瘤的发生与发展机制。