血管内皮细胞生长因子与治疗性血管新生

本文概述了血管内皮细胞生长因子(VEGF)家族及其受体的组成,介绍了调控VEGF表达的因素及VEGF信号传导途径。着重阐述了VEGF促血管新生的作用机制,以及VEGF在治疗性血管新生中的研究与应用现状、存在问题及未来发展前景。还简要介绍了VEGF其他的生物学作用。     

血管内皮生长因子受体抑制剂对小鼠支气管哮喘模型气道炎症和气道重塑的影响

目的研究血管内皮生长因子(VEGF)受体抑制剂对变应性气道炎症和气道重塑的影响,阐明VEGF与支气管哮喘(简称哮喘)以及气道重塑的关系。方法BALB/c小鼠按随机数字表法分为正常对照组(A组)、哮喘模型组(B组)、VEGF受体抑制剂治疗组(C组),每组各10只。用酶联免疫吸附测定(ELISA)法对各组小鼠支气管肺泡灌洗液(BALF)和血清中VEGF进行定量分析;用免疫组化法检测VEGF在小鼠肺组织内的表达水平。采用医学图像分析软件测定支气管管壁厚度(WAt/P i)、支气管平滑肌厚度(WAm/P i)、支气管平滑肌细胞计数(N/P i)及肺组织切片中的血管计数、血管壁平滑肌厚度、血管壁平滑肌细胞计数。结果BALF中细胞总数和嗜酸粒细胞比值B组分别为(142±63)×107/L、98.0±46.9,A组分别为(30±14)×107/L、0.7±1.1,C组分别为(41±17)×107/L、4.9±3.5,A组和C组BALF中细胞总数和嗜酸粒细胞比值分别与B组比较差异有统计学意义(P均<0.01)。B组BALF中上清液和血清中VEGF水平分别为(55±26)pg/m l、(72±26)pg/m l,A组分别为(37±9)pg/m l、(49±18)pg/m l,C组分别为(34±3)pg/m l、(43±19)pg/m l,A组与B组、C组与B组间比较差异均有统计学意义(P均<0.05)。免疫组化结果显示,B组大部分支气管平滑肌、黏膜上皮细胞、肺泡上皮细胞和血管周围VEGF均呈阳性表达,而A组和C组几乎没有VEGF的表达。图像分析显示,B组WAt/P i、WAm/P i、N/P i分别为(17±5)μm2/μm、(6.3±2.2)μm2/μm、(0.050±0.020)个/μm,A组分别为(8±3)μm2/μm、(3.2±0.8)μm2/μm、(0.027±0.017)个/μm,A组与B组比较差异有统计学意义(P分别<0.01、0.05)。B组和A组血管计数分别为(19±3)个、(10±5)个,A组与B组比较差异均有统计学意义(P<0.01)。经抑制剂治疗后C组WAm/P i、血管计数分别为(4.5±1.3)μm2/μm、(11±3)个,C组与B组比较差异均有统计学意义(P均<0.05)。结论VEGF在小鼠哮喘模型气道及肺内过度表达,并参与了哮喘的发病和气道重塑过程。VEGF受体抑制剂可明显改善哮喘小鼠的变应性气道炎症和气道重塑的病理生理过程。     

Serum levels of vascular endothelial growth factor and basic fibroblast growth factor in patients with soft-tissue sarcoma

Purpose: Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been suggested to be important mediators for tumor-induced angiogenesis. We measured serum VEGF and bFGF levels from patients with soft-tissue sarcomas and correlated serum VEGF and bFGF levels with tumor status at surgery and histological grading. Materials and methods: A group of 18 healthy controls and 85 patients with soft-tissue sarcoma were enrolled in this study. The patients were classified according to tumor status at surgery. Serum levels of VEGF and bFGF were also correlated with histological grading. VEGF and bFGF levels were determined by enzyme-linked immunosorbent assay (Quantikine R&D Systems). Results: Serum VEGF and bFGF levels were significantly elevated in the patient group (VEGF: 580pg/ml, bFbF: 21pg/ml, P = 0.0001). The highest concentrations of serum VEGF and bFGF were found in patients with macroscopic tumor lesions or G3 histology. Serum VEGF levels showed a statistically significant correlation with tumor status and grading (P = 0.006 for tumor status, P = 0.0001 for grading). Conclusions: This study reveals that elevated preoperative serum VEGF and bFGF levels can be detected in the majority of patients with soft-tissue sarcoma. The significant correlation with tumor mass and histological grading suggests that a consecutive monitoring of VEGF and bFGF in the serum of patients with soft-tissue sarcoma might be a valuable marker for tumor follow-up. Received: 26 April 1999 / Accepted: 17 May 1999     

血管内皮生长因子与慢性阻塞性肺疾病的肺血管重构

血管内皮生长因子（VEGF）具有促进血管内皮细胞增殖和血管生成的作用。研究表明，VEGF在慢性阻塞性肺疾病（COPD）的肺血管重构中起着重要作用，进而加重其气道阻力和气道炎症，影响COPD的预后。如何使VEGF保持一个合适的水平有待于我们进一步的研究。     

Vascular endothelial growth factor family of ligands and receptors: review

VEGF signaling often represents a critical rate-limiting step in physiological angiogenesis. The VEGF family comprises seven secreted glycoproteins that are designated VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, placental growth factor (PlGF) and VEGF-F. The VEGF family members bind their cognate receptors. The receptors identified so far are designated VEGFR-1, VEGFR-2, VEGFR-3 and the neuropilins (NP-1 and NP-2). We review in this article the biology of the VEGF ligands and the receptors.     

Vascular endothelial growth factor in colorectal cancer

Background Angiogenesis plays an important role in colorectal cancer progression. Evidence from preclinical and clinical studies indicates that vascular endothelial growth factor (VEGF) is the predominant angiogenic factor in human colorectal cancer and is associated with formation of metastases and poor prognosis. Based on these results it was hypothesized that attacking one or more of the VEGF-mediated mechanisms may be promising in the treatment of colorectal cancer.Aims This article reviews the role of VEGF in colon cancer and summarizes recent advances in the treatment of colorectal cancer by anti-VEGF strategies.M. Guba and H. Seeliger contributed equally to this paper     

Serum vascular endothelial growth factor: a prognostic factor in cervical cancer

Purpose  To study pre-treatment serum VEGF of patients with invasive cervical cancer and its possible role as prognostic indicator. Methods  VEGF was measured using ELISA in the largest patient group (n = 167) to date. Reults  Serum VEGF was significantly higher in advanced tumor stage (P = 0.01), large tumor size (tumors larger than 2 cm) (P = 0.03), and the presence of vascular space invasion (P = 0.05). Serum VEGF was associated with disease free and overall survival [DFS: Hazard Ratio (HR) = 2.61; 95% CI 1.32–5.17; P = 0.006; for OS: HR = 2.09; 95% CI 1.54–2.84; P < 0.001, respectively]. In multivariate Cox regression serum VEGF retained its prognostic value for DFS (HR = 2.10, P = 0.03) and OS (HR = 1.92, P = 0.04). Conclusions  Serum VEGF levels correlate with more advanced and more aggressive disease in cervical cancer and may be a useful prognostic factor in patients with cervical cancer.     

Correlation between synovial blood flow signals and serum vascular endothelial growth factor levels in patients with refractory rheumatoid arthritis

The objective of the study is to examine the relationship between synovial blood flow signals and vascular endothelial growth factor (VEGF) involved in angiogenesis by Doppler ultrasound. Twenty-one patients meeting the diagnostic criteria of the American College of Rheumatology (ACR) were enrolled in this study. Doppler ultrasound signals of blood flow in the wrist synovial membrane were measured and classified into three grades: grade 1 = no flow; grade 2 = mild flow; grade 3 = intense flow. A significant correlation was observed between blood flow signals in the wrist synovial membrane and serum VEGF levels (r = 0.5681, P = 0.0072). These results suggest that the measurement of Doppler ultrasound signals of blood flow in the wrist synovial membrane is useful in the evaluation of angiogenesis.     

血管内皮生长因子在支气管哮喘小鼠气道中表达变化及其对气道重构的影响

目的研究血管内皮生长因子（VEGF）在支气管哮喘（哮喘）小鼠气道中表达变化及其对气道重构的影响。方法将40只雌性BALB/c小鼠随机分为4组（每组10只）：生理盐水对照组（A组）;哮喘组（B组）;VEGF受体抑制剂干预组（C组）;地塞米松干预组（D组）。用鸡卵白蛋白致敏和雾化激发建立慢性哮喘小鼠模型。收集小鼠的支气管肺泡灌洗液（BALF）,行白细胞和嗜酸粒细胞（EOS）计数;ELISA法检测BALF和血清中VEGF的水平;用SABC免疫组化法检测VEGF在肺组织的表达水平并行抗Ⅷ因子免疫组化染色在显微镜下计数气管黏膜固有层、黏膜下层血管密度;用逆转录-聚合酶链反应（RT-PCR）方法检测VEGF mRNA的表达变化;采用医学图像分析软件测定支气管管壁厚度（WAt/Pbm）及肺组织切片中的血管数。结果B组BALF中白细胞总数、EOS百分比、VEGF浓度及血清中VEGF浓度明显高于A组,差异有统计学意义（P〈0.01）;C、D两组与B组比较差异均有统计学意义（P〈0.01）,C组与D组比较差异无统计学意义（P〉0.05）。抗Ⅷ因子免疫组化染色及图像分析结果显示：B组气管血管密度、WAt/Pbm及肺组织切片中的血管数明显高于A组（P〈0.01）,C、D两组与B组比较均显著减少（P〈0.01）,C组与D组比较差异无统计学意义（P〉0.05）。免疫组化及RT-PCR检测结果显示：B组小鼠肺组织中的VEGF表达较A组显著增加（P〈0.01）,C、D两组小鼠肺组织中VEGF的表达与B组比较均显著减少（P〈0.01）,C组与D组比较差异无统计学意义（P〉0.05）。结论VEGF在小鼠哮喘模型气道及肺组织内过度表达,参与了哮喘的发病和气道重构的过程,VEGF受体抑制剂可以降低哮喘模型的气道炎症,减轻气道重构的程度。     

血管内皮生长因子及其受体与非小细胞肺癌血管新生

肿瘤生长和转移都依赖于新生血管的形成.血管内皮生长因子(vascular endothelial growth factor,VEGF)是血管新生最重要的诱导因子.不同VEGF及其受体的亚型功能相异.目前,对VEGF信号转导通路机制的研究取得了很大进展.通过阻断VEGF的某些环节来抑制血管新生的靶向治疗成为非小细胞肺癌的治疗热点.     

神经生长因子在哮喘患者诱导痰炎性细胞的表达

目的　通过观察神经生长因子 (NGF)在哮喘气道炎性细胞的表达 ,探讨NGF与哮喘气道炎症形成的关系。方法　取 11例哮喘急性发作期、19例哮喘非急性发作期患者及 11例健康对照者的诱导痰 ,其中 12例哮喘非急性发作期患者予丙酸氟替卡松 (ICS)治疗 2周后再取诱导痰。做诱导痰炎性细胞分类计数 ;SP法测诱导痰炎性细胞NGF表达 ;ELISA测其上清中白细胞介素 (IL) 5浓度。结果　 (1)诱导痰巨噬细胞、淋巴细胞、粒细胞NGF表达阳性率哮喘组较健康对照组高 (P值均<0 0 1) ,且急性发作期较非急性发作期高 (P <0 0 1)。急性发作期IL 5水平较非急性发作期和健康对照组高 (P值均 <0 0 1)。 (2 ) 12例非急性发作期患者经ICS治疗后 ,诱导痰巨噬细胞、淋巴细胞、粒细胞NGF表达阳性率及IL 5水平均较治疗前下降 (P值均 <0 0 1)。 (3)巨噬细胞、粒细胞NGF表达阳性率与淋巴细胞相对计数构成比、IL 5水平均呈正相关。结论　哮喘患者气道内巨噬细胞、淋巴细胞和粒细胞NGF表达增加 ,提示NGF可能与哮喘气道炎症的形成有关。     

血管内皮生长因子与支气管哮喘

血管内皮生长因子(VEGF),又称血管渗透因子(VPF),是一种广泛存在于机体组织的细胞因子,参与体内多种疾病过程,本文就VEGF的生物学特性及其与支气管哮喘的关系进行综述。     

外源性碱性成纤维细胞生长因子对血管性痴呆患者血管内皮生长因子的影响

目的 研究外源性碱性成纤维细胞生长因子对血管性痴呆患者用药前后血清血管内皮生长因子的影响。方法 选择血管性痴呆患者60例、采用临床痴呆评定量表(CDR)筛选出轻度血管性痴呆患者60例,分成轻度痴呆治疗组34例,轻度痴呆对照组26例,正常对照组30例,通过给予患者外源性碱性成纤维细胞生长因子氧气雾化吸入,分别对各组患者治疗前、治疗后14d、30d及正常对照组血清血管内皮生长因子的观察。结果 两组患者治疗前血清血管内皮生长因子明显低于正常对照组,痴呆治疗组患者治疗后14d、30d 血清血管内皮生长因子逐渐升高,与痴呆对照组相比有统计学意义(P<0.001)。结论 外源性碱性成纤维细胞生长因子通过鼻黏膜进入中枢神经系统,促进血清血管内皮生长因子的生成,从而表明bFGF可能可诱导脑内神经元发生,达到治疗目的。     

哮喘患者痰液中炎症介质和细胞因子与气道重塑的关系研究

目的　以支气管粘膜网状基底膜厚度作为气道重塑的指标 ,探讨哮喘患者气道重塑与痰液中细胞因子和炎症介质的关系。方法　对 2 0例哮喘患者和 10名正常对照者经纤维支气管镜行(纤支镜 )支气管粘膜活检 ,测量支气管粘膜网状基底膜厚度 ,用荧光酶联免疫方法测定痰液中的嗜酸细胞阳离子蛋白 (ECP) ,酶联免疫法测定白细胞介素 5 (IL 5 )、肿瘤坏死因子 (TNF α)的水平 ;采用SPSS8 0统计软件作等级相关分析 ,探讨哮喘患者痰液中ECP、IL 5、TNF α水平与支气管粘膜厚度的关系。结果　缓解期哮喘患者支气管粘膜网状基底膜厚度为 (10 1± 2 6 ) μm ,与正常对照组 [(4 4± 1 2 )μm]比较 ,差异有显著性 (P <0 0 0 5 ) ;哮喘组痰液中ECP水平为 (14 4± 80 ) μg/L、IL 5为 (17± 4 ) μg/L、TNF α为 (14 6± 79) μg/L ,与正常对照组 [(81± 4 4 ) μg/L、(14± 4 ) μg/L、(5 3± 36 ) μg/L]比较 ,差异有显著性 (P <0 0 0 5 ) ;两组痰液中ECP、IL 5与支气管粘膜厚度呈明显正相关 (r =0 5 6 9、0 4 6 6 ,P均 <0 0 0 5 ) ;两组痰液中TNF α水平与粘膜厚度无明显相关 (r=0 2 5 4 ,P >0 0 5 )。结论　缓解期哮喘患者支气管粘膜网状基底膜厚度均存在不同程度增厚 ;而痰液ECP和IL 5水平与支气管粘膜厚度呈     

血管内皮生长因子与胸腔积液

血管内皮生长因子（VEGF）是目前已知活性最强、高度特异的血管生长因子。研究表明：VEGF可使血管通透性增加、渗出增多，在促进胸腔积液形成的过程中起重要作用。深入研究VEGF为进一步认识胸腔积液的发病机制及发展新的治疗策略提供了条件。     

Levels of vascular endothelial growth factor and hepatocyte growth factor in sera of patients with rheumatic diseases

Abstract

Angiogenesis plays an important role in the progression of rheumatic disease. We measured the levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in sera from patients with rheumatic diseases and investigated whether these angiogenic factors would be useful in the evaluation of rheumatic diseases. Serum VEGF and HGF levels were determined using ELISA in 128 patients with rheumatic diseases and in 11 healthy controls. Serum VEGF and HGF levels were significantly higher in patients with rheumatic diseases compared to healthy controls [VEGF, 312 ± 20?pg/ml versus 61 ± 8?pg/ml (mean ± SE), P < 0.001; HGF, 935 ± 36?pg/ml versus 413 ± 49?pg/ml, P < 0.01]. Serum VEGF and HGF levels were significantly elevated in patients with adult Still's disease (VEGF, 1021 ± 258?pg/ml; HGF, 1500 ± 295?pg/ml) and were relatively increased in patients with active rheumatoid arthritis (RA) (VEGF, 359 ± 94?pg/ml) and systemic sclerosis (SSc) (VEGF, 356 ± 43?pg/ml; HGF, 1294 ± 224?pg/ml). HGF levels correlated with the clinical course and disease severity in rheumatic disease patients. VEGF levels correlated with the presence of Raynaud's phenomenon (P < 0.05), interstitial lung disease (ILD) (P < 0.05), and serum KL-6 levels (P < 0.01), whereas HGF levels correlated with cryoglobulinemia (P < 0.05), ILD (P < 0.05), serum C-reactive protein (CRP) (P < 0.05), thrombomodulin (P < 0.05), and KL-6 levels (P < 0.05) in rheumatic disease patients. VEGF levels correlated with the skin scores and KL-6 levels in SSc patients and also correlated with the disease activity of RA patients. These data suggest that serum VEGF and HGF levels are related to rheumatic disease activity and the presence of complications. Analysis of VEGF and HGF may be useful in the clinical evaluation of rheumatic disease patients.     

Vascular endothelial growth factor as a survival factor for human islets: effect of immunosuppressive drugs

Aims/hypothesis Rapamycin, part of the immunosuppressive regimen of the Edmonton protocol, has been shown to inhibit vascular endothelial growth factor (VEGF) production and VEGF-mediated survival signalling in tumour cell lines. This study investigates the survival-promoting activities of VEGF in human islets and the effects of rapamycin on islet viability. Materials and methods Levels of VEGF and its receptors in isolated human islets and whole pancreas was determined by western blotting and immunostaining. Islet viability following VEGF or immunosuppressive drug treatment was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Islet VEGF release was measured by ELISA. Mouse islets infected with an adenovirus expressing the gene for VEGF were transplanted syngeneically into streptozotocin-induced diabetic mice, with blood glucose levels measured three times per week. Results Isolated human islets produced multiple isoforms of VEGF and VEGF receptors 1, 2 and 3 and the coreceptor neuropilin 1. Exogenous VEGF (10 ng/ml) prevented human islet death induced by serum starvation, which suggests that VEGF can act as a survival factor for human islets. Transplantation of mouse islets infected with a VEGF-expressing adenovirus in a syngeneic model, improved glycaemic control at day 1 post-transplantation (p < 0.05). Rapamycin at 10 and 100 ng/ml significantly reduced islet VEGF release (by 37 ± 4% and 43 ± 6%, respectively; p < 0.05) and at 100 ng/ml reduced islet viability (by 36 ± 9%) and insulin release (by 47 ± 7%, all vs vehicle-treated controls; p < 0.05). Tacrolimus had no effect on islet VEGF release or viability. Conclusions/interpretation Our data suggest that rapamycin may have deleterious effects on islet survival post-transplantation, both through a direct effect on islet viability and indirectly through blockade of VEGF-mediated revascularisation.     

血管内皮生长因子与脑梗死

血管内皮生长因子(vascular endothelial growth factor,VEGF)是血管内皮细胞的一种特异性促分裂原,是最重要的促血管新生因子.VEGF在脑梗死后高度表达,在血管新生和神经保护中起着重要作用;同时,其过度表达也会使血管通透性增加,进而可能加重脑水肿.文章对VEGF及其受体与脑梗死的研究进展进行了综述.     

Vascular endothelial growth factor and tryptase changes after chemoembolization in hepatocarcinoma patients

AIM: To evaluate vascular endothelial growth factor(VEGF) and tryptase in hepatocellular cancer(HCC)before and after trans-arterial chemoembolization(TACE).METHODS: VEGF and tryptase serum concentrations were assessed from 71 unresectable HCC patients before and after hepatic TACE performed by binding DC-Beads?to doxorubicin. VEGF levels were examined for each serum sample using the Quantikine Human VEGF-enzyme-linked immuno-absorbent assay(ELISA),whereas tryptase serum concentrations were assessed for each serum sample by means of fluoro-enzyme immunoassay(FEIA) using the Uni-CAP100 tool.Differences between serum VEGF and tryptase values before and after TACE were evaluated using Student t test. Person's correlation was used to assess the degree of association between the two variables.RESULTS: VEGF levels and serum tryptase in HCCpatients before TACE had a mean value and standard deviation(SD) of 114.31 ± 79.58 pg/mL and 8.13± 3.61 μg/L, respectively. The mean levels and SD of VEGF levels and serum tryptase in HCC patients after TACE were 238.14 ± 109.41 pg/mL and 4.02 ±3.03 μg/L. The changes between the mean values of concentration of VEGF and tryptase before treatment and after treatment was statistically significant(P 0.000231 and P 0.00124, by Wilcoxon-Mann-Whitney respectively). A significant correlation between VEGF levels before and after TACE and between tryptase levels before and after TACE was demonstrated(r =0.68, P = 0.003; r = 0.84, P = 0.000 respectively).CONCLUSION: Our pilot results suggest that the higher serum VEGF levels and the lower tryptase levels following TACE may be potential biomarkers changing in response to therapy.