血管内皮生长因子及其受体表达和侵袭性垂体腺瘤血管生成关系的研究

目的研究血管内皮生长因子(VEGF)及其受体Flt-1在人垂体腺瘤中的表达,探讨其表达变化、微血管密度(MVD)与侵袭性垂体腺瘤血管生成的关系.方法采用免疫组织化学技术检测52例垂体腺瘤的VEGF及其受体表达水平,同时检测CD34表达,用于测定垂体腺瘤的MVD,比较其在侵袭性和非侵袭性垂体腺瘤中的差异.结果VEGF及其受体和MVD与垂体腺瘤的侵袭性密切相关(P＜0.01).结论VEGF可能通过促进新生血管形成刺激垂体腺瘤生长和侵袭,其作用机制有待进一步研究.     

Survivin、VEGF、MVD的表达与垂体腺瘤侵袭性的关系

目的探讨凋亡抑制基因Survivin、血管内皮生长因子（VEGF）、微血管密度（MVD）的表达与垂体腺瘤侵袭性的关系。方法采用免疫组化S-P法检测上述三者在50例垂体瘤中的表达。结果侵袭组和非侵袭组的Survivin、VEGF、MVD表达均有显著性差异,Survivin的高表达将直接导致血管发生显著增强,其高表达与肿瘤细胞的侵袭性呈正相关．VEGF具有促进肿瘤新生血管形成的作用,MVD则是血管形成的量化指标。结论Survivin、MVD、VEGF可作为判断垂体腺瘤侵袭性和评估预后的良好生物学指标。     

垂体腺瘤血管生成与VEGF、bFGF和内皮抑素的关系探讨

目的检测垂体腺瘤组织中的血管内皮细胞生长因子(VEGF)、碱性成纤维细胞生长因子(bFGF)和内皮抑素蛋白的表达,探讨其与垂体腺瘤血管生成的关系及临床意义。方法采用免疫组织化学技术检测了46例垂体腺瘤标本中VEGF、bFGF和内皮抑素的蛋白表达,以VIII因子相关抗原(FⅧ-Rag)血管内皮细胞标记法作为血管密度(MVD)计数的方法,分析上述血管生成相关因子与垂体腺瘤血管生成的关系。结果VEGF、bFGF蛋白表达与MVD之间呈显著正相关(p<0.05),内皮抑素蛋白表达和MVD之间无显著相关性(P>0.05)。结论垂体腺瘤血管生成与促血管生成因子VEGF、bFGF蛋白水平表达的上调有关。     

MMP-9、VEGF和p16在垂体腺瘤中的表达及其与该腺瘤侵袭性的相关性研究

目的研究基质金属蛋白酶-9(MMP-9)、血管内皮细胞生长因子(VEGF)和p16在侵袭性和非侵袭性垂体腺瘤中的表达及其与垂体腺瘤侵袭性的相关性。方法用免疫组化方法检测MMP-9、VEGF和p16在30例侵袭性和24例非侵袭性垂体腺瘤中的表达水平,并分析其垂体腺瘤侵袭性的关系。结果 MMP-9、VEGF标记指数在侵袭性垂体腺瘤中分别为(39.44±5.61)%和(24.28±3.94)%,均较非侵袭性垂体腺瘤中的(22.17±4.32)%和(17.62±1.89)%显著增高(P0.01)。p16在非侵袭性垂体腺瘤中的标记指数为(27.49±4.07)%,较侵袭性垂体腺瘤的标记指数(20.18±3.26)%显著增高(P0.01)。垂体腺瘤的侵袭性与MMP-9和VEGF的表达呈正相关(P0.05),而与p16表达呈负相关(P0.05)。结论 MMP-9、VEGF的表达增高和p16的表达降低与垂体腺瘤的侵袭性密切相关。     

VEGF在人脑胶质瘤中的表达与肿瘤增殖及肿瘤血管生成的关系

目的研究血管内皮细胞生长因子(vascular endothelial growth factor,VEGF)在人脑胶质瘤中的表达与肿瘤增殖及血管生成的关系。方法应用免疫组化技术和形态定量分析法,检测98例手术切除脑胶质瘤中VEGF表达、PCNA标记指数(PCNA LI)、微血管密度(Microvessel density,MVD)表达。结果(1)肿瘤细胞及血管内皮细胞均可以表达VEGF,阳性颗粒分布于肿瘤胞浆中;(2)高级别肿瘤PCNA、LI、MVD显著高于低级别肿瘤(P<0.05);VEGF表达阳性肿瘤的PCNA、LI、MVD显著高于VEGF表达阴性肿瘤(P<0.05);(3)在星形细胞肿瘤中,随着MVD的增大,VEGF在肿瘤血管内皮的染色率逐渐增加,与肿瘤的MVD存在正相关关系(r值为0.44,P<0.01)。结论脑胶质瘤的VEGF表达与MVD呈正相关关系,VEGF在肿瘤细胞增殖及血管再生过程中起重要作用。     

VEGF、PCNA、Ki-67、P53表达与垂体腺瘤侵袭性的相关研究

目的 研究VEGF、PCNA、Ki-67、P53在垂体腺瘤中的表达,探讨其与垂体腺瘤侵袭性的关系.方法 采用SP免疫组化技术,检测45例垂体腺瘤中VEGF、PCNA、Ki-67、P53的表达,并计数MVD,结合影像、手术及病理结果等进行统计学分析.结果 (1)垂体腺瘤中VEGF、PCNA、P53表达在非侵袭性与侵袭性组之间差异有统计学意义(P＜0.05),Ki-67在非侵袭性与侵袭性组之间无统计学意义(χ2=0.020,P＞0.05);(2)垂体腺瘤中VEGF、MVD的表达与垂体腺瘤病理分型之间有一定关系,在垂体腺瘤PRL病理型组中有统计学意义(χ2=9.396,P＜0.05),PCNA、P53、Ki-67的表达在病理分型PRL、GH组中无统计学意义.结论 (1)VEGF、PCNA、P53的表达在非侵袭性与侵袭性组之间有统计学意义,可作为判断垂体腺瘤侵袭性的重要指标;Ki-67的表达在非侵袭性与侵袭性组之间无统计学意义,Ki-67更多地反映恶性肿瘤的增殖性及预后;(2)VEGF、MVD在垂体腺瘤PRL病理型组中有统计学意义,PCNA、P53、Ki-67在病理分型PRL、GH组中无统计学意义,提示血管密度的改变不能完全代表垂体腺瘤的侵袭性,或者仅在垂体腺瘤某些病理型中可以代表一定的侵袭性.     

微血管密度及血管内皮生长因子表达与垂体瘤侵袭性的关系

目的探索垂体瘤微循环与侵袭性的关系及其临床意义。方法采用免疫组化技术检测了42例垂体瘤中血管内皮生长因子(VEGF)蛋白表达,同时染色VonWillebrand因子显示血管内皮细胞以检测肿瘤内微血管密度MVD,分析VEGF蛋白表达及MVD与垂体瘤海绵窦侵袭性的关系。结果VEGF蛋白表达和MVD与垂体瘤的海绵窦侵袭性均有关(两者均P<0.001)。结论VEGF与新生血管形成在垂体瘤的侵袭性生物学行为中具有重要的作用。     

VEGF、uPA在侵袭性垂体腺瘤中的表达及意义

目的探讨血管内皮生长因子（VEGF）、尿激酶型血纤溶酶原激活剂（uPA）在侵袭性垂体腺瘤和非侵袭性垂体腺瘤中的表达及其临床意义。方法应用免疫组化法检测26例侵袭性垂体腺瘤和20例非侵袭性垂体腺瘤中VEGF、uPA的表达，并结合临床资料分析。结果VEGF和uPA在侵袭性垂体腺瘤的表达明显高于在非侵袭性垂体腺瘤中的表达，VEGF和uPA的表达水平与垂体腺瘤的侵袭性正相关。其中uPA在垂体腺瘤中的表达强度高于VEGF。结论VEGF和uPA与垂体腺瘤侵袭性生长及复发相关。     

PTTG、MMPs、VEGF在侵袭性垂体腺瘤中的表达及其意义

目的研究垂体瘤转化基因（PTTG）蛋白、基质金属蛋白酶（MMPs）和血管内皮生长因子（VEGF）在垂体腺瘤中的表达及其相关性,以及它们与垂体腺瘤生物学行为的关系。方法垂体腺瘤组织标本50例,其中侵袭性26例,非侵袭性24例,利用免疫组化Envision二步法检测并分析比较PTTG、MMP-2、MMP-9及VEGF在侵袭性垂体腺瘤和非侵袭性垂体腺瘤中的表达。结果侵袭性垂体腺瘤中PTTG、MMP-2、MMP-9及VEGF的表达均高于非侵袭性垂体腺瘤（P〈0.05）;在侵袭性垂体腺瘤中PTTG和VEGF与MMP-2、MMP-9的表达水平均呈正相关（P〈0.01）。结论垂体腺瘤的侵袭性与PTTG、MMPs、VEGF的过度表达有关,PTTG、MMPs可作为辅助诊断侵袭性垂体腺瘤的一项生物学指标。     

垂体腺瘤中MMP-9与VEGF的表达及其与侵袭性的关系

目的探讨基质金属蛋白酶-9(MMP-9)与血管内皮生长因子(VEGF)在垂体腺瘤中的表达及其与垂体腺瘤侵袭性的关系。方法应用免疫组化染色法和逆转录聚合酶链式反应(RT-PCR)方法检测侵袭性(20例)和非侵袭性(10例)垂体腺瘤组织标本中MMP-9与VEGF的表达,分析二者与垂体腺瘤侵袭性的关系及二者的相关性。结果侵袭性垂体腺瘤组MMP-9、VEGF的蛋白及mRNA表达均较非侵袭性腺瘤组显著增高(P<0.01)。在蛋白水平,侵袭性腺瘤组中MMP-9与VEGF表达水平无显著性相关;在mRNA水平,侵袭性腺瘤组中MMP-9与VEGF表达水平成正相关(P<0.05)。结论侵袭性垂体腺瘤的生物学行为与MMP-9基因表达增高及血管生成正调节因子VEGF表达上调有关。MMP-9与VEGF在新生血管形成过程中存在着内在联系。     

Immunohistochemical detection of vascular endothelial growth factor (VEGF) in the vasculature of oligodendrogliomas

C. Christov, H. Adle-Biassette, C. Le Guerinel, S. Natchev and R. K. Gherardi (1998) Neuropathology and Applied Neurobiology 24, 29–35 Immunohistochemical detection of vascular endothelial growth factor (VEGF) in the vasculature of oligodendrogliomas Vascular endothelial growth factor (VEGF) appears to be implicated in tumour angiogenesis. In the present study immunohistochemical expression of VEGF was evaluated in 34 oligodendrogliomas (13 grade II, 21 grade III [WHO]). VEGF immunoreactivity was found in 31 of 34 cases. Expression of VEGF was observed in endothelial cells and some vascular smooth muscle cells, but not in neoplastic oligodendrocytes. Vessel counts, percentages of VEGF-positive vessels and vessels with vascular endothelial proliferation were assessed. The degree of VEGF labelling and vascular-endothelial proliferation in each vessel were evaluated using a 3 degree intensity score. Expression of VEGF was higher in grade III than in grade II oligodendrogliomas as assessed by percentage of VEGF positive vessels (55.8 ± 29.2% vs 17.0 ± 19.0% [P < 0.001]) and by VEGF immunostaining intensity (1.90 ± 0.60 vs 0.90 ± 0.40 [P < 0.001]). VEGF expression did not correlate with vessel density. Intensity of VEGF expression correlated positively with that of vascular-endothelial proliferation in grade III tumours (r=+0.47 [P < 0.05]). The percentage of VEGF positive vessels showed some degree of positive correlation with the percentage of vessels showing vascular-endothelial proliferation (r=+408 [P < 0.10]). Within individual grade III tumours 67.5 ± 29.6% of all vessels with vascular-endothelial proliferation were VEGF-positive and 31.0 ± 20.5% of all VEGF-positive vessels showed no evidence of vascular-endothelial proliferation. We conclude that (i) expression of VEGF is observed in the vasculature of oligodendrogliomas; (ii) marked expression of VEGF is observed in grade III oligodendrogliomas; (iii) VEGF may be one of the interrelated causative stimuli acting in concert to induce vascular-endothelial proliferation.     

胶质瘤中促血管生成素2和血管内皮生长因子基因表达的意义

目的 探讨胶质瘤促血管生成素（Ang2）和血管内皮细胞生长因子（VEGF）基因表达的意义。方法 采用逆转录-酶促链反应（RT-PCR）检测52例人脑胶质瘤中Ang2、VEGF基因的表达，同时采用SABC免疫组化方法检测Ang2蛋白的表达。结果 50例脑胶质瘤表达Ang2 mRNA片段．52例脑胶质瘤表达VEGF mRNA片段。Ang2 mRNA与VEGF mRNA表达呈显著性正相关（r=0，816，P〈0．01）；高度恶性胶质瘤Ang2mRNA、VEGF mRNA表达均显著性高于低度恶性者（P〈0．01）。免疫组化染色显示Ang2蛋白主要分布在高度恶性胶质瘤组织的瘤细胞和内皮细胞．而在低度恶性胶质瘤中呈低水平表达。结论 Ang2与VEGF可能在胶质瘤血管生成中起协同性促进作用。     

纤维蛋白对大鼠脑血管内皮细胞血管内皮生长因子表达的影响

目的观察纤维蛋白对大鼠脑血管内皮细胞血管内皮生长因子(VEGF)转录及蛋白水平表达的影响。方法大鼠脑血管内皮细胞分离后培养,加入不同浓度的纤维蛋白,通过Real-time PCR检测VEGF转录水平,应用酶联免疫方法(ELISA)定量检测培养基和细胞裂解液中的VEGF水平。结果纤维蛋白可以特异性诱导大鼠脑血管内皮细胞表达VEGF;加入不同浓度的纤维蛋白(0.03mg/ml、0.1mg/ml、0.3mg/ml和1.0mg/ml),24h后,1.0mg/ml纤维蛋白组的培养基VEGF水平显著增高(P<0.001);1.0mg/ml纤维蛋白与大鼠脑血管内皮细胞分别培养0、2、4、8、24、48h,VEGF浓度在共培养2h已经升高,8h时显著升高,在24h时仍然保持在显著升高表达水平(P<0.005),48h有所下降;Real-time PCR结果提示,大鼠脑血管内皮细胞中VEGF mRNA的上调呈现出剂量和时间依赖性增加。结论纤维蛋白可以上调大鼠血管内皮细胞中的VEGF。     

Role of vascular endothelial growth factor in neuronal DNA damage and repair in rat brain following a transient cerebral ischemia

The antisense knockdown technique and confocal laser scanning microscopic analysis were used to elucidate vascular endothelial growth factor (VEGF) induction and its effect on DNA damage and repair in rat brain following a transient middle cerebral artery occlusion. Immunohistochemical study and in situ hybridization showed that the expression of VEGF and its mRNA was enhanced in the ischemic core and penumbra of ischemic brain. Western blot analysis further illustrated that VEGF induction was time-dependently changed in these areas. Double-staining analysis indicated that VEGF-positive staining existed in the neuron, but not in the glia, and it colocalized with excision repair cross-complementing group 6 (ERCC6) mRNA, a DNA repair factor. VEGF antisense oligodeoxynucleotide infusion reduced VEGF induction and resulted in an enlargement of infarct volume of the brain caused by ischemia. Moreover, it also increased the number of DNA damaged cells and lessened the induction of ERCC6 mRNA in ischemic brains. These results suggest that the induction of endogenous VEGF in ischemic neurons plays a neuroprotective role probably associated with the expression of ERCC6 mRNA.     

VEGF和透明质酸酶在侵袭性垂体腺瘤中的表达研究

目的探讨血管内皮细胞生长因子（VEGF）和透明质酸酶在侵袭性垂体腺瘤中的表达及其意义。方法2004年1月至2010年12月收集手术切除垂体腺瘤标本70例,其中侵袭性垂体腺瘤36例,非侵袭性垂体腺瘤34例,另收集12例正常脑组织标本作为对照。应用免疫组化法检测标本中VEGF蛋白质表达,用逆转录聚合酶链式反应检测标本中VEGF和透明质酸酶基因PH-20mRNA表达,用酶联免疫吸附法测定标本中透明质酸酶活性。结果在侵袭性垂体腺瘤中VEGF蛋白质和mRNA、透明质酸酶活性及其基因PH-20mRNA的表达水平分别为（2．52±0．32）分、1．72±0．23、（10．99±3．79）mU／g和1．60±0．28,在非侵袭性垂体腺瘤中分别为（1．56±0．68）分、0．97±0．50、（4．29±1．86）mU／g和0．41±0．19,在正常脑组织中则分别为（0．11±O．09）分、0．08±0．04、（4．10±1．96）mU／g和0．00±0．00。在侵袭性垂体腺瘤组织中VEGF蛋白质和mRNA、透明质酸酶活性及其基因PH-20mRNA表达均显著高于在非侵袭性垂体腺瘤中的表达（P〈0．05）,而在非侵袭性垂体腺瘤中的表达又明显高于在正常脑组织中的表达（P〈0．05）。结论VEGF、透明质酸酶与垂体腺瘤的侵袭性密切相关,对侵袭性垂体腺瘤的诊断及预后判断有重要价值。     

bFGF、VEGF在大鼠创伤海马脑组织中的表达

目的 研究碱性成纤维细胞生长因子(bFGF)和血管内皮细胞生长因子(VEGF)在大鼠创伤海马组织中不同时间的表达及其它们之间的关系，从分子水平探讨颅脑损伤后的病理机制，为临床治疗脑损伤的新途径提供实验基础。方法 改进Marmarou大鼠加速弥漫性脑损伤模型，取海马区创伤脑组织免疫组化染色观察bFGF、VEGF基因表达情况。结果 海马CAl区伤后6h，bFGF基因表达增加，12h达高峰；VEGF基因表达伤后24h达高峰，72h回复到对照水平。结论 bFGF、VEGF基因表达与脑损伤密切相关，作为生长因子，bFGF、VEGF可能参与颅脑损伤后神经元保护及损伤后修复过程。     

局灶性脑缺血大鼠血管内皮生长因子的表达及意义

目的 :研究大鼠局灶性脑缺血后血管内皮细胞生长因子 (VEGF)表达的动态变化。方法 :采用尼龙线栓法制作大鼠局灶性永久性大脑中动脉闭塞模型 ,用免疫组织化学方法观察大鼠缺血后 3、6、12h和 1、2、3、7d时 ,VEGF表达的情况。结果 :大鼠缺血后 3h ,缺血侧脑组织开始出现VEGF表达 ,2 4h明显增多 ,2d达高峰 ,7d时仍有少量表达。各时间占VEGF的表达主要集中在梗死灶周围。结论 :VEGF可能参与缺血性脑损伤的病理发展及修复过程     

Regulatory effect of vascular endothelial growth factor on blood spinal cord barrier in presyrinx state of experimental syringomyelia

BACKGROUND:Vascular endothelial growth factor (VEGF) is able to regulate blood spinal cord barrier function as well as influence neovascularization and cause edema. OBJECTIVE: Through establishment of a rabbit model of syringomyelia,to explore the correlation between VEGF protein and mRNA expressions and function of blood spinal cord barrier and edema degree of spinal cord in presyrinx state. DESIGN,TIME AND SETTING: Randomized controlled animal study was performed in the Tumor Institute of the Fourth Hospi...     

Low serum VEGF levels are associated with Alzheimer's disease

OBJECTIVE: As vascular endothelial growth factor (VEGF) determines important neurotrophic and neuroprotective actions, we postulated serum VEGF levels could be abnormally low in patients with Alzheimer's disease (AD). METHODS: We measured serum VEGF levels (VEGF(165) isoform by ELISA) in 51 patients with AD by National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorder Association criteria and compared with 66 age- and gender-matched non-demented controls. Patients with AD were stratified into levels of dementia severity by the Clinical Dementia Rating scale. Serum VEGF levels were stratified into upper (>309 pg/ml), middle (207-309 pg/ml), and lower (<207 pg/ml) tertiles. VEGF (-2,578) (rs 699,947) and VEGF (-634) (rs 2,010,963) polymorphisms were genotyped in patients with AD and controls. RESULTS: The mean concentration of VEGF in the serum of patients with AD (215.9 pg/ml, SD 101.5) was significantly lower than that of the controls (308.6 pg/ml, SD 223.9, P = 0.004), and decreased serum VEGF levels were associated with AD in a dose-dependent manner, the lower tertile of serum VEGF levels being associated with a fivefold increased risk for AD when compared with the upper tertile. There was no significant correlation between serum VEGF levels and age, sex, APOE alleles, AD dementia severity nor VEGF gene polymorphisms. CONCLUSION: Decrease in serum VEGF levels could contribute to the neurodegenerative process in AD.     

Retrovirus producer cells encoding antisense VEGF prolong survival of rats with intracranial GS9L gliomas

With increasing size tumors are continually dependent on a functional blood vessel system to guarantee the supply with oxygen and nutrients. Vascular endothelial growth factor (VEGF) is a key mediator not only of developmental but also of hypoxia-mediated and tumor-induced angiogenesis. Gene therapy using antisense VEGF with the aim to inhibit tumor angiogenesis may be a successful strategy for the treatment of highly vascular and invasive malignant gliomas. We investigated whether retrovirus producer cells encoding antisense VEGF can be used for in vivo gene transfer. The full length mouse VEGF164 cDNA was cloned in a sense and antisense direction into the retroviral expression vector pLEN. pLEN-VEGF (sense) and pLEN-FGEV (antisense) expression vectors were used to transfect the packaging cell line GP + E86 and to establish ecotropic virus producer cell lines. GP + E86:LEN-FGEV (#5) cells showed high expression of antisense VEGF mRNA, whereas GP+ E86:LEN-VEGF (#8) showed high expression of sense VEGF mRNA and active VEGF protein. Co-implantation of GS-9L cells with retrovirus producing cells containing the antisense VEGF construct into the brains of syngeneic rats showed a statistically significant inhibition of tumor growth and prolongation of survival time, while co-implantation of retrovirus producer cells containing the sense VEGF expression vector resulted in an increasing tumor growth and reduced survival time of the rats compared to control animals. Histological analysis of the tumors co-implanted with GP + E86:LEN-FGEV (#5) cells showed the suppression of angiogenesis, high degree of necrosis and no evidence of a significant immune response. Expression of antisense VEGF mRNA in these tumors was confirmed by in situ hybridization analysis. This is the first report demonstrating the potential utility of virus producer cells as in vivo gene transfer vehicles for antisense VEGF gene therapy of malignant gliomas.