沙利度胺治疗急性白血病的疗效及对血管调控因子水平的影响

目的 观察沙利度胺联合化疗治疗急性白血病的临床疗效及其对血浆血管内皮生长因子(VEGF)、血管内皮生长因子受体(VEGFR)、碱性成纤维细胞生长因子(bFGF)水平的影响.方法 急性白血病患者36例,随机分为试验组及对照组各18例.每组均予以常规化疗方案标准剂量化疗,试验组同时口服沙利度胺100 mg/d.治疗前及治疗后8周分别采集外周血,双抗体夹心酶联免疫吸附法(ELISA)检测血浆VEGF、VEGFR、bFGF含量.以15位健康体检者为健康对照组.结果 试验组与对照组有效率分别为88.9%(16/18)和77.8%(14/18),差异有统计学意义(x2=4.103,P＜0.05).试验组与对照组治疗前血浆VEGF水平分别为(389.78±249.94)和(318.54±125.78)pg/ml,高于健康组的(132.91±26.66)pg/ml(t=3.141、3.024,均P＜0.01);治疗后分别为(211.74±36.72)和(288.02±31.77)pg/ml,高于健康组(t=2.413、2.324,均P＜0.05);试验组与对照组治疗前VEGF差异无统计学意义(t=1.384,P＞0.05),治疗后差异有统计学意义(t=2.793,P＜0.05).试验组与对照组治疗前血浆VEGFR水平分别为(2490.75±1695.9)和(2322.78±1105.87)pg/ml,高于健康组的(1134.98±378.45)pg/ml(t=2.914、2.783,均P＜0.01);治疗后分别为(1359.71±390.24)和(1753.89±337.04)pg/ml,与健康组相比差异有统计学意义(t=2.572、2.447,均P＜0.05);试验组与对照组治疗前VEGFR差异无统计学意义(t=1.276,P＞0.05),治疗后差异有统计学意义(t=2.486,P＜0.05).试验组与对照组治疗前血浆bFGF水平分别为(2.43±0.27)和(2.4l±0.33)ng/ml,高于健康组的(1.83±0.44)ng/ml(t=4.982、4.171,均P＜0.05);治疗后分别为(2.09±0.17)和(2.11±0.31)ng/ml,与健康组相比差异有统计学意义(t=3.01l、2.773,均P＜0.05);试验组与对照组治疗前及治疗后相比差异无统计学意义(t=0.953、1.282,均P＞0.05).结论 沙利度胺联合化疗可提高急性白血病患者的缓解率,有可能成为一种通过抗血管新生从而抑制白血病细胞生长及浸润的有效治疗方法.     

三氧化二砷抑制淋巴瘤细胞株血管内皮生长因子表达的研究

目的 探讨三氧化二砷(ATO)对人类淋巴瘤细胞株内血管内皮生长因子(VEGF)表达的影响.方法 应用实时荧光定量聚合酶链(Real-time PCR)技术及酶联免疫吸附(ELISA)法检测ATO作用前后淋巴瘤细胞株Raji及Jurkat内VEGF基因及其蛋白表达量的变化.结果 在ATO诱导淋巴瘤细胞株凋亡过程中,两种细胞未经ATO处理前均高表达VEGF mRNA(Raji加药2 μmol/L 12 h △△ Ct值0.75±0.15,Jurkat加药3.5 μmol/L 72 h △△ Ct值1.67±0.13)及VEGF蛋白(加药12 h,Raji198.38±4.37;Jurkat 563.11±3.81),且Jurkat细胞较Raji细胞的VEGF蛋白的表达量高;经ATO作用24、48、72 h后VEGF的mRNA表达量均较加药前明显减少(加药72 h △△Ct值,Raji:8.95±0.38;Jurkat:9.09±0.16),差异有统计学意义(t=3.54,P<0.01;t=3.65,P<0.01);同时蛋白表达量也较加药前明显减少(加药72 h,Raji:23.55±2.06;Jurkat:57.11±3.88),差异有统计学意义(t=2.48,P<0.05;t=2.59,P<0.05),且两者与药物作用时间明显相关,各时间点之间蛋白表达量差异均有统计学意义(F=2.47,P<0.05;F=2.50,P<0.05).结论 ATO通过阻断淋巴瘤细胞生长所需的血管条件,从而抑制淋巴瘤细胞的增殖.     

DLL4、HES1、VEGF-C及VEGFR-2在白血病患者骨髓中的表达及其临床意义

目的 探讨白血病患者骨髓中DLL4、HES1、VEGF-C及VEGFR-2的mRNA表达水平检测的临床意义,为白血病的诊治提供新的思路。方法选取白血病患者59例作为病例组,均根据临床表现、血象、骨髓象、细胞化学染色、细胞遗传学及流式细胞术检查确诊;对照组20例为营养性贫血患者。采用半定量反转录聚合酶链反应( RT-PCR)方法测定DLL4、HES1、VEGF-C、VEGFR-2 mRNA的含量。结果各组初发急性和慢性白血病患者骨髓中DLL4、HES1、VEGF-C、VEGFR-2mRNA的表达与对照组相比均显著升高(P＜0.05)。急性白血病缓解后DLL4、HES1、VEGFR-2的mRNA表达高于对照组( P= 0.041、0.016、0.047)。急性髓系白血病(AML)组DLL4与VEGFR-2、HES1与VEGF-C表达呈正相关(r= 0.424、0.472;P=0.030、0.014);慢性淋巴细胞白血病(CLL)组HES1与VEGF-C表达呈正相关(r= 0.997,P=0.042)。急性白血病伴髓外浸润者VEGF-CmRNA的表达高于不伴髓外浸润者(P=0.022)。AML组VEGF-C mRNA的表达与原始细胞数呈正相关(r=0.315,P=0.024)。结论DLL4、HES1、VEGF-C及VEGFR-2在白血病发病中相互作用,促进白血病发展、转移及浸润,且这些因子在不同类型白血病及髓外浸润中的作用存在差异。     

重组腺病毒介导血小板衍生生长因子感染人类脐带间质干细胞的实验研究

目的 检测重组腺病毒方法介导血小板衍生生长因子(PDGF)对人类脐带间质干细胞(MSC)的感染能力,为将其用于基因治疗奠定基础.方法 反转录-聚合酶链反应(RT-PCR)法扩增人类PDGF的cDNA序列,构建重组病毒载体AdPDGF.分离培养人类脐带MSC.体外以不同感染复数感染MSC后,流式细胞术检测感染效率,荧光显微镜观察绿色荧光蛋白(GFP)表达.锥虫蓝染色及四甲基偶氮唑蓝(MTT)法检测感染后细胞生存活力及增殖能力.酶联免疫吸附(ELISA)法检测细胞上清液中PDGF分泌水平.结果 成功构建病毒载体AdPDGF.其对MSC的感染效率随感染复数增加而增高,当感染复数为50时,达到最高,为87.36%.未感染的MSC、感染AdPDGF和对照病毒的MSC活力分别为(97.8 ±2.3)%、(91.9 ±4.0)%和(92.8 ±4.0)%.增殖能力分别为(100 ±16.8)%,(95.9±12.0)%和(87.5±9.7)%,感染AdPDGF的MSC与两个对照比较差异均无统计学意义(P>0.05).感染48 h后MSC能有效分泌PDGF,感染复数为10、30、50时,PDGF分泌水平分别为(1.53±0.37)、(3.03 ±0.68)和(5.25±0.92)ng/ml,MSC-GFP及MSC组未检测到有PDGF分泌.结论 成功构建AdPDGF重组腺病毒并高效感染人类脐带MSC.     

多发性骨髓瘤患者基质细胞衍生因子-1α、CD44v6表达的研究

目的 探讨基质细胞衍生因子-1α(SDF-1α)、CD44v6(一种变异的CD44受体)在多发性骨髓瘤(MM)中的表达水平及其与病情进展的关系.方法 用酶联免疫吸附试验(ELISA)检测24例MM患者[14例初发和复发MM患者(初发和复发MM组),10例病情稳定MM患者(病情稳定MM组)]和15位健康骨髓移植供者或非肿瘤良性贫血患者(对照组)的骨髓单个核细胞(MNC)和骨髓基质细胞(BMSC)培养上清的SDF-1 α、CD44v6水平.结果 初发和复发MM组MNC培养上清的SDF-1α、CD44v6表达水平[(7232.41±2644.97)pg/ml和(34.34±13.20)ng/ml]显著高于病情稳定MM组[(2315.49±748.29)pg/ml和(15.69±5.28)ng/m1](t=6.25、t=7.82;均P＜0.05)和对照组[(1149.52±636.06)pg/ml和(4.85±3.62)ng/ml](t=4.60、t=7.61;均P＜0.05).病情稳定MM组SDF-1α、CD44v6水平显著高于对照绀(t=2.99、t=4.87;均P＜0.05).9例初发和复发MM组的BMSC与人类骨髓瘤细胞系细胞U266加入rhIL-6进行混合培养后,SDF-1 α水平[(6180.25±5925.38)pg/ml]显著高于5例对照组BMSC[(1021.13±358.65)pg/ml]和9例初发和复发MM组[(1004.07±727.36)pg/ml](t=2.66、t=2.42;均P＜0.05).而其他BMSC各组问的SDF-1α水平差异无统计学意义(P＞0.05).SDF-1 α与CD44v6两者表达水平呈正相关(r=0.51,P=0.03).结论 SDF-1 α、CD44v6水平升高与MM的病情进展或发病有关,也可能与MM的肿瘤浸润过程有关;而这些体内过程可能需骨髓瘤细胞和BMSC与IL-6、SDF-1α和CD44v6等因素协同完成.     

地西他滨联合三氧化二砷对NB4细胞凋亡作用的研究

目的 研究去甲基化制剂地西他滨(DAC)单用或联合三氧化二砷(As2O3)对NB4细胞凋亡的作用机制.方法 将不同浓度的DAC、As2O3以及两药联合作用于NB4细胞,不加药为对照组,采用四甲基偶氮唑蓝(MTT)法检测细胞增殖抑制作用,流式细胞术检测细胞凋亡.结果 DAC与As2O3单药对NB4细胞的抑制作用呈浓度时间依赖性(DAC 1 μmol/L作用24、48、72 h的抑制率分别为12.18%、22.72%、35.54%;DAC 2 μmol/L作用24、48、72 h的抑制率分别增高为22.14%、31.18%、45.21%;As2O3 0.5 μmol/L作用24、48、72 h的抑制率分别21.09%、32.43%、44.93%;As2O3 1.0 μmol/L作用24、48、72 h的抑制率分别增高为31.69%、41.12%及54.27%),两药联合抑制作用较单药明显(DAC 1 μmol/L+As2O3 0.5 μmol/L作用24、48、72 h抑制率分别为42.10%、48.75%、60.78%)(P<0.05),各浓度组与对照组比较差异均有统计学意义(P值均<0.05);As2O3 1 μmol/L作用于NB4细胞株48 h可见5.8%的细胞凋亡,联合组增高为17.3%.结论 DAC能显著抑制NB4细胞的增殖并诱导其凋亡,DAC联合As2O3对NB4细胞增殖抑制及诱导凋亡有协同作用.     

硼替佐米作用不同时间对K562耐药细胞株核因子-κ B途径的影响

目的 观察硼替佐米(商品名:万珂,PS-341)对柔红霉素(DNR)诱导的K562耐药细胞株(K562/DNR)核因子-κ B(NF-κ B)、抑制蛋白κ B(I κ B)及P-糖蛋白(P-gp)表达的影响,探讨PS-341逆转耐药的分子机制.方法 以100μg/ml DNR单用或联合应用4μg/L PS-341分别作用于K562/DNR 12、24及36 h,检测不同时间点各组NF-κ B、Iκ B及P-gp表达情况,同时测定NF-κ B p65活性,检测各组细胞凋亡率.结果 Western blot结果显示:与阴性对照组相比,DNR可诱导NF-κ B表达上调及活性增强、I κ B表达下调、P-gp表达上凋;加用PS-341可显著抑制DNR诱导的NF-κ B及P-gp表达,使I κ B表达增加.加用PS-341后,NF-κ B活性12 h为(15.3±1.87)%[DNR组为(23.8±2.27)%],24 h为(10.2±1.69)%[DNR组为(25.4±1.98)%],36 h为(6.08±2.53)%[DNR组为(26.9±2.58)%],与相应单用DNR组相比均有明显下降,差异有统计学意义(P值均＜0.05).DNR与PS-341联用后,细胞凋亡率12 h为(35.23±5.15)%[DNR组为(15.56±4.12)%],24 h为(40.26±6.89)%[DNR组为(17.25±2.89)%],36 h为(43.58±7.69)%[DNR组为(22.47±4.58)%],与DNR组相比,细胞凋亡率均明显增加,差异具有统计学意义(P值均＜0.05).上述作用呈时间依赖性.结论 PS-341可减少K562/DNR细胞NF-κ B的活化,降低P-gp表达,逆转细胞耐药,促进细胞凋亡.     

健康人外周血树突状细胞的体外诱导及其功能分析

目的 分析以健康人AB血清与rhCD40L体外诱导健康人外周血树突状细胞(DC)的功能.方法 对健康人外周血单个核细胞进行体外培养,在以健康人AB血清为基础的培养体系中加入粒细胞巨噬细胞集落刺激因子(GM-CSF)、重组人白细胞介素(rhIL)-4、rhCD40L等细胞因子,诱导单个核细胞分化形成DC,采用倒置显微镜及瑞特-吉姆萨染色观察,流式细胞术行DC表型鉴定,四甲基偶氮唑蓝比色(MTT)法进行混合淋巴细胞反应(MLR),检测其抗原刺激能力,酶联免疫吸附(ELISA)法检测DC培养上清IL-12的分泌.结果 培养7 d后的细胞具有典型的DC形态,并上调表达DC特征性表面分子CD83及共刺激分子CD40、CD80、CD86,第0、1、3、5、7天,5个时间点间CD83、CD40、CD80、CD86、CD14表达差异有统计学意义(F值分别为50.253、243.769、248.181、191.267、226.339,均P＜0.05).培养后的DC可较强地刺激同种自体淋巴细胞增殖,GM-CSF加rhIL-4、rhCD40L组较GM-CSF加rhIL-4组刺激反应能力强.培养的DC自培养第5天始即有IL-12分泌,未加CD40L组IL-12 p40分泌量为(42.92±1.54)pg/ml,加CD40L组为(136.18±5.27)pg/ml;培养第7天,IL-12 p40分泌明显增多,两组分别为(60.09±2.27)pg/ml及(322.30±30.60)pg/ml,差异有统计学意义(t=-44.941、-22.611,均P＜0.05).结论 健康人外周血单个核细胞可在以健康人AB血清与rhCD40L为主的培养体系中诱导成DC.     

HIF-1α和VEGF-C在胆囊癌中的表达及相关性

目的:探讨缺氧诱导因子-1α(hypoxia inducible factor-1α,HIF-1α)和血管内皮生长因子C(vascular endothelium growth factor-C,VEGF-C)在胆囊癌组织中的表达情况及相关性.方法:应用免疫组织化学方法检测胆囊癌组织HIF-1α和VEGF-C表达的情况,分析二者在胆囊癌组织表达的相关性.结果:胆囊癌组织中HIF-1α和VEGF-C的表达比慢性胆囊炎组织的表达差异明显,显著升高(X2=20.136和21.231,P均<0.05).胆囊癌组织中HIF-1α和VEGF-C的表达呈正相关(r＝0.586,P＜0.05).结论:胆囊癌组织中普遍存在HIF-1α和VEGF-C的表达,HIF-1α与VEGF-C的表达呈高度正相关.     

甲氰菊酯和溴氰菊酯对黔东南田鱼(鲤)的急性毒性与安全评价

采用常温半静态停食试验法,进行甲氰菊酯和溴氰菊酯对黔东南田鱼(鲤)的急性毒性试验.结果表明,在(22.8±0.1)℃下,甲氰菊酯和溴氰菊酯对鲤24h LC50分别为28.480和6.135μl/L,48h LC50分别为26.919和5.826μl/L,96h LC50分别为26.793和5.382μl/L;安全浓度分别为6.819和1.497μl/L.根据安全浓度的大小,可知鲤对溴氰菊酯的敏感性大于对甲氰菊酯的敏感性.建议稻田养鱼的甲氰菊酯和溴氰菊酯使用量分别控制在安全浓度即6.819和1.497μl/L以内.     

Transforming growth factor beta 1 down-regulates vascular endothelial growth factor receptor 2/flk-1 expression in vascular endothelial cells

Although the importance of the vascular endothelial growth factor (VEGF)/VEGF tyrosine kinase receptor (VEGFR) system in angiogenesis is well established, very little is known about the regulation of VEGFR expression in vascular endothelial cells. We have cloned partial cDNAs encoding bovine VEGFR-1 (flt) and -2 (flk-1) and used them to study VEGFR expression by bovine microvascular- and large vessel-derived endothelial cells. Both cell lines express flk-1, but not flt. Transforming growth factor beta 1 (TGF-beta 1) reduced the high affinity 125I-VEGF binding capacity of both cell types in a dose-dependent manner, with a 2.0-2.7-fold decrease at 1-10 ng/ml. Cross-linking experiments revealed a decrease in 125I-VEGF binding to a cell surface monomeric protein corresponding to Flk-1 on the basis of its affinity for VEGF, molecular mass (185-190 kDa), and apparent internalization after VEGF binding. Immunoprecipitation and Western blot experiments demonstrated a decrease in Flk-1 protein expression, and TGF-beta 1 reduced flk-1 mRNA levels in a dose-dependent manner. These results imply that TGF-beta 1 is a major regulator of the VEGF/Flk-1 signal transduction pathway in endothelial cells.     

Role of vascular endothelial cell growth factor in Ovarian Hyperstimulation Syndrome

Controlled ovarian hyperstimulation with gonadotropins is followed by Ovarian Hyperstimulation Syndrome (OHSS) in some women. An unidentified capillary permeability factor from the ovary has been implicated, and vascular endothelial cell growth/permeability factor (VEGF) is a candidate protein. Follicular fluids (FF) from 80 women who received hormonal induction for infertility were studied. FFs were grouped according to oocyte production, from group I (0-7 oocytes) through group IV (23-31 oocytes). Group IV was comprised of four women with the most severe symptoms of OHSS. Endothelial cell (EC) permeability induced by the individual FF was highly correlated to oocytes produced (r2 = 0.73, P < 0.001). Group IV FF stimulated a 63+/-4% greater permeability than FF from group I patients (P < 0. 01), reversed 98% by anti-VEGF antibody. Group IV fluids contained the VEGF165 isoform and significantly greater concentrations of VEGF as compared with group I (1,105+/-87 pg/ml vs. 353+/-28 pg/ml, P < 0. 05). Significant cytoskeletal rearrangement of F-actin into stress fibers and a destruction of ZO-1 tight junction protein alignment was caused by group IV FF, mediated in part by nitric oxide. These mechanisms, which lead to increased EC permeability, were reversed by the VEGF antibody. Our results indicate that VEGF is the FF factor responsible for increased vascular permeability, thereby contributing to the pathogenesis of OHSS.     

Hypoxia and vascular endothelial growth factor stimulate angiogenic integrin expression in bovine retinal microvascular endothelial cells

PURPOSE: Integrins alphavbeta3 and alphavbeta5 are cell-to-matrix adhesion molecules that have been reported to mediate vascular cell proliferation and migration. The authors investigated the regulation of expression of these angiogenic integrins by hypoxia and vascular endothelial growth factor (VEGF) in retinal microvascular endothelial cells in culture. METHODS: Cultured bovine retinal capillary endothelial cells were exposed to human recombinant VEGF under normoxic (95% air, 5% CO2) conditions to assess the effects of VEGF. Hypoxia studies were performed under lower oxygen concentration (0.5%-1.5% O2) induced by nitrogen replacement in constant 5% CO2 conditions. Integrin family mRNA and protein expression were assessed by northern blot analysis and immunoprecipitation. RESULTS: VEGF (25 ng/ml) increased integrin alphav, beta3, and 35 mRNA after 24 hours 6.1+/-0.8-fold (P < 0.001), 5.9+/-1.1-fold (P < 0.001), and 1.9+/-0.2-fold (P < 0.01), respectively. Similarly, hypoxia stimulated gene expression of integrin alphav and beta3 after 24 hours by 5.1+/-1.7-fold (P < 0.01) and 3.0+/-0.5-fold (P < 0.01), respectively, and integrin beta5 after 9 hours 1.4+/-0.2-fold (P < 0.05). This hypoxia-induced, integrin alphav mRNA elevation was inhibited significantly by anti-VEGF neutralizing antibody. Also, a conditioned medium from confluent endothelial cells maintained under hypoxic conditions for 24 hours produced a 7.1+/-1.1-fold increase (P < 0.001) in integrin alphav mRNA expression after 24 hours, which was reversed by anti-VEGF neutralizing antibody. Induction of integrin alphav by VEGF and hypoxia was confirmed in the protein level. CONCLUSIONS: These data suggest that hypoxia stimulates expression of vascular integrins alphavbeta3 and alphavbeta5 in retinal microvascular endothelial cells partially through autocrine-paracrine action of VEGF induced by the hypoxic state.     

Hypoxia induces vascular endothelial growth factor gene and protein expression in cultured rat islet cells

The formation of new microvasculature by capillary sprouting at the site of islet transplantation is crucial for the long-term survival and function of the graft. Vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen with potent angiogenic and vascular permeability-inducing properties, may be a key factor in modulating the revascularization of islets after transplantation. In this study, we examined the gene expression of VEGF mRNA in three tumor cell lines and in isolated whole and dispersed rat islets in vitro by Northern blot hybridization in normoxic (5% CO2, 95% humidified air) and hypoxic (1% O2, 5% CO2, 94% N2) culture conditions. Increased expression of VEGF mRNA was observed in beta-TC3, RAW 264.7, and IC-21 tumor cell lines when subjected to hypoxia. With isolated whole islets in normoxic culture, a threefold increase in VEGF mRNA (P < 0.001) was seen at 48 h as compared with freshly isolated islets. This response was similar to the 3.8-fold increase observed with islets subjected to hypoxia. Dispersed rat islet cell clusters cultured on Matrigel for 24 h under hypoxic conditions showed a 3.4-fold increase (P < 0.01) in VEGF mRNA compared with those cultured in normoxia. This correlated with increased VEGF secretion as determined by enzyme-linked immunosorbent assay. Immunohistochemical studies revealed the presence of increased expression of VEGF protein near the center of islets after 24 h of normoxic culture. Islet cell clusters on Matrigel showed intense cellular localization of VEGF in both beta-cells and non-beta-cells. These findings suggest that rat islet cells, when subjected to hypoxia during the first few days after transplantation, may act as a major source of VEGF, thereby initiating revascularization and maintaining the vascular permeability of the grafted islets.     

Role of vascular endothelial growth factor on erythropoietin-related endothelial cell proliferation

The vascular actions of recombinant human erythropoietin (rhEPO) are of particular relevance for fully understanding rhEPO effects. This study examines the mechanisms of action of rhEPO on endothelial cells from bovine aorta (BAEC). First, the studies demonstrated that rhEPO acts on BAEC proliferation as a comitogenic growth factor in the presence of fetal calf serum (FCS). The main experimental findings disclosed that an interaction between rhEPO and vascular endothelial growth factor (VEGF) is instrumental for the growth-promoting action of rhEPO, as shown by the blockade (92.8+/-2.2% inhibition, P < 0.01) of the rhEPO-induced BAEC proliferation by a specific anti-VEGF antibody and by the capability of VEGF for substituting FCS in the induction of rhEPO-related BAEC proliferation (increase in BAEC number in the absence of FCS: 20 U/ml rhEPO alone, 0.3+/-2.8%; 5 x 10(-11) M VEGF alone, 52.9+/-3.1%; 20 U/ml rhEPO + 5 X 10(-11) M VEGF, 117.8+/-6.9%, P < 0.01 between the two agents combined with respect to each agent alone). The existence of a positive interaction between rhEPO and VEGF was further demonstrated by observing an increased cytosolic Ca2+ ([Ca2+]i) mobilization response to VEGF (10(-11)M) in BAEC pretreated or not with 20 U/ml rhEPO (delta[Ca2+]i = 704+/-111 versus 246+/-36 nM, respectively, P < 0.01). To further examine the mechanism of the potentiation of VEGF effect by rhEPO, we analyzed the mRNA expression of the VEGF receptors KDR/flk-1 and flt-1. The results disclosed that BAEC pretreatment with rhEPO upregulated the expression of both KDR/flk-1 and flt-1, therefore providing a structural basis for the aforementioned positive interactions between VEGF and rhEPO. Furthermore, inhibition by genistein suggests that tyrosine phosphorylation was involved in the VEGF receptor upregulation. The mechanisms identified in the present study disclose an interaction at the level of mRNA expression and functional effects between a hormone with predominantly hemopoietic effects, namely, erythropoietin, and an angiogenic factor, namely, VEGF. This relationship between rhEPO and VEGF might be of particular importance in neovascularization processes and in patients receiving rhEPO as a treatment.