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.     

Role of circulating vascular endothelial growth factor and hepatocyte growth factor in patients with coronary artery disease

Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are thought to stimulate endothelial cell proliferation and induce angiogenesis in vivo. However, the precise mechanism responsible for VEGF and HGF release in patients with coronary artery disease is still unknown. We studied serum concentrations of VEGF and HGF in 20 patients with acute myocardial infarction (AMI), 20 patients with stable angina pectoris (AP) who had reversible perfusion defects on stress myocardial scintigraphy, and 16 patients with old myocardial infarction (OMI) who had no reversible defects on stress myocardial scintigraphy. The control group consisted of 20 patients with atypical chest pain who had angiographically normal coronary arteries. Serum VEGF and HGF concentrations were measured by enzyme-linked immunosorbent assay. Both the serum VEGF and HGF concentrations in the early stage of myocardial infarction in the patients with AMI were higher than those in the patients with AP and with OMI, and control patients. The VEGF concentration in the patients with AP was higher than in the patients with OMI, whereas the HGF concentration did not differ in the patients with AP and OMI. The VEGF concentration in AMI patients who had had preinfarction angina on admission was higher than that of patients who had had no preinfarction angina, whereas the HGF concentration did not differ between the two groups of patients. These results suggest that the serum VEGF concentration may reflect myocardial ischemia to a greater degree than the serum HGF concentration. Received June 9, 2000 / Accepted September 30, 2000     

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.     

Elevated hepatocyte growth factor in sera from patients with insulin-dependent diabetes mellitus

Hepatocyte growth factor (HGF) is a pleiotropic cytokine known to be involved in tissue regeneration and repair. We measured serum levels of HGF in patients with insulin-dependent diabetes mellitus (type 1). The patients were divided into four groups: (1) 10 patients at clinical presentation before insulin treatment; (2) 19 patients with newly diagnosed type 1 diabetes (diabetes duration 1/2–3 years); (3) 14 patients with long-standing type 1 diabetes without renal involvement (diabetes duration >10 years, and urinary albumin excretion (UAER) <20 μg/ min); and (4) 20 patients with long-standing type 1 diabetes with renal involvement (diabetes duration >10 years and UAER 20–500 μg/min). Sera from 24 age- and sex-matched healthy blood donors constituted a control group. The HGF levels of the four groups were (mean±SD); group 1, 0.74±0.14; group 2, 0.78±0.40; group 3, 0.86±0.42; group 4, 0.79±0.27 ng/ml, compared to 0.43±0.24 ng/ml in the control group (P<0.0008). HGF levels were not significantly different between the four patient groups. The elevated serum HGF levels did not correlate with complications related to type 1 diabetes, such as UAER, retinopathy and macrovascular complications, suggesting that HGF levels were not associated with the type 1 diabetes complications. In conclusion, our results show that type 1 diabetic patients have increased serum HGF levels compared with controls and that HGF is elevated to the same extent in newly diagnosed as well as in long-standing type 1 diabetes. Received: 29 November 1997 / Accepted in revised form: 11 March 1998     

Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma

Angiogenesis is a crucial process in growth and progression of cancer and there is growing evidence that neovascularisation is important in hematological malignancies. Since an increased angiogenic potential has been identified in multiple myeloma, we simultaneously measured circulating serum levels of the cytokines bFGF, VEGF, HGF and IL-6 by ELISA in 67 patients with multiple myeloma or monoclonal gammopathies of undetermined significance (MGUS) and in 20 controls. Median values of bFGF were 4.7 pg/ml in healthy volunteers, 6.2 in MGUS, 6.3 in myeloma stage I, 13.4 in stage II and 21.7 in stage III. Myeloma patients had significantly higher bFGF serum levels than controls (p<0.001). Pretreatment bFGF levels differed significantly in the Salmon and Durie stages I-III (p=0.02) and were significantly elevated in stage II-III compared to stage I myeloma (p=0.02). In patients responding to chemotherapy according to the CLMTF criteria, a significant decrease in serum bFGF, VEGF and HGF levels occurred (median pretreatment values for bFGF 23.9 pg/ml, post-treatment 6.5 pg/ml; p<0.001, for VEGF 223 pg/ml versus 105 pg/ml; p=0.02 and for HGF 1429 pg/ml versus 1077 pg/ml; p=0.02, respectively). In 11 patients who did not achieve a remission, there was no significant decrease in bFGF, VEGF and HGF levels. These data show that myeloma in stages II and III is associated with an increase in serum bFGF concentrations and give the first report that effective chemo-therapy is accompanied by a significant decrease in the angiogenic factors bFGF, VEGF and HGF, while no decrease of these factors could be found in nonresponders.     

MSCs transfected with hepatocyte growth factor or vascular endothelial growth factor improve cardiac function in the infarcted porcine heart by increasing angiogenesis and reducing fibrosis

Background

Cell transplantation and gene therapy have been demonstrated to have beneficial effects after a myocardial infarction (MI). Here, we used a large animal model of MI to investigate the beneficial effects of mesenchymal stem cells (MSCs) transfected with hepatocyte growth factor (HGF) or vascular endothelial growth factor (VEGF) genes.

Methods

A porcine MI model was created by balloon occlusion of the distal left anterior descending artery for 90 min followed by reperfusion. At 1 week after MI, the pigs were infused via the coronary vein with saline (n = 8), MSCs + AdNull(n = 8), MSC + VEGF(n = 10), or MSC + HGF(n = 10). Cardiac function and myocardial perfusion were evaluated by using echocardiography and gated cardiac perfusion imaging before and 4 weeks after transplantation. Morphometric and histological analyses were performed.

Results

All cell-implanted groups had better cardiac function than the saline control group. There were further functional improvements in the MSC + HGF group, accompanied by smaller infarct sizes, increased cell survival, and less collagen deposition. Blood vessel densities in the damaged area and cardiac perfusion were significantly greater in the MSC + AdNull group than in the saline control group, and further increased in the MSC + VEGF/HGF groups. Tissue fibrosis was significantly less extensive in the MSC and MSC + VEGF groups than in the saline control group and was most reduced in the MSC + HGF group.

Conclusion

MSCs (alone or transfected with VEGF/HGF) delivered into the infarcted porcine heart via the coronary vein improved cardiac function and perfusion, probably by increasing angiogenesis and reducing fibrosis. MSC + HGF was superior to MSC + VEGF, possibly owing to its enhanced antifibrotic effect.     

血管内皮生长因子对腹水性质的诊断价值

目的　探讨腹水中血管内皮生长因子 (VEGF)测定在良恶性腹水鉴别诊断中的价值 ,以及联合检测癌胚抗原 (CEA)的临床意义。方法　于 2 0 0 2 - 0 5～ 2 0 0 3- 0 2采用酶联免疫吸附法检测苏州大学附属第一医院住院患者 5 8例腹水中的VEGF、CEA质量浓度。结果　恶性腹水VEGF含量明显高于良性腹水 ,差异有显著性 (P <0 0 1)。联合测定腹水VEGF和CEA质量浓度 ,其诊断恶性腹水的敏感性较单独腹水CEA检测有明显提高 ,差异有显著性 (P <0 0 5 )。结论　腹水VEGF测定有助于良恶性腹水的鉴别诊断 ,联合检测腹水VEGF和CEA对于腹水的鉴别诊断更有临床实用价值。     

老年大鼠心肌缺血后VEGF及其亚型的表达

目的探讨老年急性心肌缺血后VEGF各亚型表达特点,为老年心血管疾病的促血管生成治疗奠定基础。方法复制老龄大鼠心肌梗死模型,采用RT-PCR技术同管扩增VEGF和内参基因,比较VEGF各亚型与内参基因的比值,VEGF120、164、188的和为总VEGF。结果老年大鼠心脏总VEGFmRNA在缺血各阶段明显少于年青大鼠(P<0.01),而且达到峰值的时间推迟,老年大鼠第6小时总VEGFmRNA与GAPDH的比值(2.86±0.19)明显低于年青大鼠第3小时的比值(6.09±0.30)(P<0.001)。缺血后各时间点年青和老年大鼠的VEGF164所占比例最高,VEGF120最低。老年大鼠VEGF188的表达比例增加。结论老年大鼠心肌缺血后VEGF表达减少,而且没有血管生成活性的VEGF188所占比例增加,可能导致老年缺血心肌血管生成能力下降。     

Plasma vascular endothelial growth factor in Japanese Type 2 diabetic patients with and without nephropathy

Aim: To determine whether plasma vascular endothelial growth factor (VEGF) level is elevated in Type 2 diabetic patients with an early stage of diabetic nephropathy. Methods: We studied 71 Japanese Type 2 diabetic patients with normal serum creatinine level (<100 μmol/l) (age 63.0 [60.3–65.6] years old, diabetes duration 15.6 [14.0–17.3] years, HbA1c 7.36% [7.06–7.66%], mean [95% confidence interval, CI]): normoalbuminuric patients (n=36); microalbuminuric patients (n=21); and proteinuric patients (n=14). Plasma VEGF concentration was measured by a quantitative sandwich enzyme immunoassay technique. Results: Plasma VEGF concentration was not related to the degree of albuminuria: normoalbuminuric patients (25 [13–95] ng/l, median [25th–75th percentile]); microalbuminuric patients (33 [15–120] ng/l); and proteinuric patients (54 [17–107] ng/l). Plasma VEGF level in patients with retinopathy (25 [15–95] ng/l, n=30) was not elevated as compared to those without retinopathy (53 [14–126] ng/l, n=34). Plasma VEGF tended to correlated negatively with diabetes duration (R's=−.217, P=.0690) and HbA1c (R's=−.221, P=.0647), whereas there was no correlation between plasma VEGF level and age, serum creatinine or urinary albumin to creatinine ratio (ACR) of the patients, respectively. Plasma VEGF level in the group of patients with HbA1c equal to or below the median (<7.2%) was significantly higher than that in the group of patients with HbA1c above the median (>7.2%) (P<.05). Conclusions: The results suggested that Type 2 diabetic patients with microalbuminuria and those with retinopathy are not necessarily associated with an elevation of circulating plasma VEGF concentration. Plausible association between plasma VEGF level and glycemic control remains to be seen.     

呼出气冷凝液中VEGF的检测在肺部疾病中的研究进展

呼出气冷凝液（EBC）检测是一种用来检测呼吸道生物标记物的新技术,具有无创、操作简单、可重复进行等特点。血管内皮生长因子（VEGF）是反映肺部疾病炎症反应及氧化应激变化的标志物之一。现就EBC的收集、VEGF相关生物学特性及在肺部疾病中检测EBC中VEGF水平的临床研究进展进行综述。     

VEGF-A及其受体在多种恶性血液病中的研究进展

血管内皮生长因子A(VEGF-A)是一种具有血管通透性的糖蛋白,属血管内皮生长因子家族中的一员,通过与靶器官相应的受体结合发生二聚体化和自身磷酸化发挥作用。VEGF-A可协同其它细胞因子促使内皮细胞的生长、增殖、迁移,导致大量新生血管的形成,为白血病细胞对淋巴网状组织的侵袭提供了充足的养分,不仅起到抑制树突细胞成熟的作用,还可以触发破骨溶骨活动及诱发破骨细胞的趋化现象,使内皮细胞和残留的基质细胞产生趋化作用。因此,在各种恶性血液病中,VEGF-A及其受体表达的高低与疾病的发生、发展、预后有着密切的联系。本文就VEGF-A及其受体与各种血液系统恶性肿瘤的相关研究进展作一综述。     

血管内皮生长因子在肺癌组织中表达的研究

目的　观察血管内皮生长因子 (VEGF)表达、肺癌组织微血管密度 (MVD)和肺癌临床病理指标及预后的关系 ,探讨VEGF的作用机制。　方法　应用免疫组化方法检测 6 0例肺癌患者肺癌组织标本MVD及VEGF的表达。　结果　①VEGF在肿瘤细胞、肺癌组织内巨噬细胞呈阳性 ,部分血管内皮细胞及成纤维细胞也呈弱阳性。②肺癌组织MVD计数在肺癌各项临床病理指标中无显著性差异 ,P >0 0 5 ;VEGF表达在不同N分期 (淋巴结转移 )及临床分期之间存在显著性差异 ( P <0 0 1,P <0 0 5 ) ,并随淋巴结转移及临床分期的进展而有逐渐增强的趋势。③血管高密度组VEGF表达阳性率为 77 4 %,明显高于血管低密度组 ( 44 8%) ,P <0 0 1。④CoxRegression风险比例模型分析 ,肺癌临床分期及VEGF表达可作为判断肺癌患者预后的独立指标。　结论　①VEGF可由肿瘤细胞、巨噬细胞及部分血管内皮细胞及成纤维细胞等多种细胞产生 ,通过旁分泌作用促进肿瘤血管生成。②VEGF在肺癌淋巴结转移及临床分期中起重要作用 ,并可作为判断肺癌患者预后的参考指标之一。     

膀胱移行细胞癌VEGF和VEGFR的表达及相关性的探讨

目的　探讨膀胱移行细胞癌 (BTCC)中血管内皮生长因子 (VEGF)及其受体 (VEGFR)的表达及与两者之间的关系。方法　采用免疫组织化学链霉菌抗生物素 过氧化物酶连接法 (S P法 )对 30例BTCC及 1 0例正常膀胱黏膜组织中VEGF及VEGFR的表达进行检测。结果　VEGF和VEGFR在绝大多数BTCC中呈阳性表达 ,平均表达率分别为 87%和 73 %。随肿瘤分期和分级的升高其表达水平升高 ,但在正常膀胱组织中未见表达。结论　BTCC中VEGF和VEGFR表达阳性 ,提示其在BTCC的血管生成和侵袭进展过程中起着重要作用 ,并将有可能为BTCC抗血管形成治疗及预防提供新的思路     

人脑胶质瘤中血管内皮细胞生长因子表达及其与细胞增殖的关系

为探讨人脑胶质瘤组织中血管内皮细胞生长因子 (VEGF)表达及其与细胞增殖的关系 ,应用链霉菌抗生物素蛋白 -过氧化物酶连接法 (SABC)免疫组织化学技术检测了 6 7例人脑胶质瘤、8例正常脑组织中 VEGF表达及增殖细胞核抗原 (PCNA)标记指数 (PCNA L I)。结果 VEGF在人脑胶质瘤组织中的阳性表达率为 83.6 %,正常脑组织中无表达 (P<0 .0 0 5 ) ;肿瘤组织中 VEGF表达与 PCNA L I呈显著正相关 (P<0 .0 0 5 )。认为胶质瘤细胞能分泌 VEGF,VEGF表达在肿瘤细胞增殖中起重要作用。     

大肠癌组织中P16蛋白和血管内皮生长因子的表达及其临床意义

目的：探讨大肠癌组织中P16蛋白和血管内皮生长因子（VEGF）表达及其临床意认。方法：用S－P免疫组织化学方法测定66例大肠癌组织和20例正常大肠组织中P16蛋白和VEGF的表达。结果：大肠癌中P16蛋白阳性率为48．5％（32／66）明显低于对照组的70．0％（14／20）（P＜0．01），VEGF阳性率为72．7％（48／66）则明显高于对照组的15．0％（3／20）（P＜0．01）：P16蛋白和VEGF在大肠癌中表达具有明显负相关性；P16蛋白和VEGF表达与大肠癌组织学类型、肿瘤直径、肿瘤部位无关（P＞0．05），而与淋巴结转移、Duke's分期五年生存率有明显的关系（P＜0．01）。结论：大肠癌中存在P16蛋白下调和VEGF上调，P16蛋白和VEGF表达可作为反映大肠癌生物学行为的指标之一。     

Platelet indices as markers of inflammation in systemic sclerosis patients: Relation to vascular endothelial growth factor and flow mediated dilatation

Aim of the work

To evaluate platelet indices in systemic sclerosis (SSc) patients and identify their clinical significance as novel inflammatory biomarkers in correlation to markers of endothelial dysfunction: vascular endothelial growth factor (VEGF) and flow mediated dilatation (FMD).

血管内皮生长因子及血管内皮生长因子受体在急性肺损伤中作用的研究

血管内皮生长因子是作用于血管内皮细胞的重要血管调节因子,它通过与内皮上的特异受体结合,可发挥促进内皮细胞增殖、分化、诱导血管生成、增加微血管通透性等多种功能.近年研究显示血管内皮生长因子在不同原因、不同阶段急性肺损伤中所起的作用不同.     

血管内皮生长因子在门脉高压患者胃黏膜的表达

目的探讨血管内皮生长因子(VEGF)在肝硬化门脉高压(PHT)患者胃黏膜的表达及其在门脉高压性胃病(PHG)发病中的作用。方法分别采集PHG、PHT和正常对照组胃黏膜组织。应用免疫组化法检测胃黏膜VEGF蛋白的表达。PHG程度按改良的McMrmark’s分级由有经验的消化科医师盲法评估。结果PHG组(49.56%±12.26%)和PHT组(48.56%±12.23%)胃黏膜VEGF表达较正常对照组(5.11%±2.14%)显著性增高(P<0.05),但前两组间VEGF的表达无统计学差异(P>0.05)。VEGF阳性表达主要见于胃小凹颈部黏膜细胞浆内。VEGF与PHG积分呈显著性正相关(H=10.592,P<0.05)。结论肝硬化门脉高压患者胃黏膜组织VEGF表达增高。PHT胃黏膜淤血、缺氧与VEGF增加存在互动关系,VEGF在PHG发病过程中的作用可能是有限的。     

Overexpression of vascular endothelial growth factor in restenoticabdominal aorta of rabbits

INTRODUCTIONVascularendothelialgrowthfactor（VEGF），alsoknownasvascularpermeabilityfactor（VPF）orvasculotropin（VAS），isa３４to４６kDahep－arin－bindingsecretedgrowthfactorthatisangiogenicinvitroandinvivo，andhasauniquetargetcellspecificityforvasculare     

Clinical significance of vascular endothelial growth factor and hepatocyte growth factor in multiple myeloma

Angiogenesis is a crucial process in the progression of multiple myeloma (MM). Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are multifunctional cytokines that potently stimulate angiogenesis including tumour neovascularization. Serum levels of VEGF and HGF were measured in 52 patients with MM by enzyme-linked immunosorbent assay (ELISA). Serum levels of VEGF and HGF were elevated in MM patients compared with healthy controls (VEGF: mean 0.31 ng/ml and 0.08 ng/ml respectively, P < 0.01; HGF: mean 2.17 ng/ml and 0.45 ng/ml, respectively, P < 0.001). In serial samples taken after chemotherapy, serum VEGF and HGF levels were correlated with M-protein levels. Serum levels of VEGF were higher in patients with extramedullary plasmacytomas than in patients without them (P < 0.05). They were also significantly higher in a group of patients who showed poor response to chemotherapy (P < 0.01). Serum levels of HGF were higher in patients with complications such as anaemia, hypercalcaemia and amyloidosis than in patients without these complications (P < 0.01, P < 0.05, P < 0.05 respectively). Both serum VEGF and HGF levels were significant predictors of mortality (P = 0.01, P = 0.02, respectively, log-rank test). The present study demonstrated that serum levels of VEGF and HGF are significantly elevated and dependent on the severity of MM, suggesting that measurement of VEGF and HGF may be useful for assessing disease progression and for predicting the response to chemotherapy in MM patients.