血管内皮细胞生长因子在急性肺损伤中的作用

急性肺损伤(acute lurg injury,ALI)和急性呼吸窘迫综合征(acute respiratory distressyndrome,ARDS)的特征性病理改变为肺毛细血管通透性增高所致的肺水肿,血管内皮细胞生长因子能抗血管内皮细胞凋亡并增加血管通透性,可能在ALI和ARDS的病理过程中起到重要作用.现对血管内皮细胞生长因子在ALI中的作用进行综述,旨在为ALI和ARDS的治疗提供新的思路.     

Pulmonary microvascular hyperpermeability and expression of vascular endothelial growth factor in smoke inhalation- and pneumonia-induced acute lung injury

Introduction

Acute lung injury (ALI) and sepsis are major contributors to the morbidity and mortality of critically ill patients. The current study was designed further evaluate the mechanism of pulmonary vascular hyperpermeability in sheep with these injuries.

Methods

Sheep were randomized to a sham-injured control group (n = 6) or ALI/sepsis group (n = 7). The sheep in the ALI/sepsis group received inhalation injury followed by instillation of Pseudomonas aeruginosa into the lungs. These groups were monitored for 24 h. Additional sheep (n = 16) received the injury and lung tissue was harvested at different time points to measure lung wet/dry weight ratio, vascular endothelial growth factor (VEGF) mRNA and protein expression as well as 3-nitrotyrosine protein expression in lung homogenates.

Results

The injury induced severe deterioration in pulmonary gas exchange, increases in lung lymph flow and protein content, and lung water content (P < 0.01 each). These alterations were associated with elevated lung and plasma nitrite/nitrate concentrations, increased tracheal blood flow, and enhanced VEGF mRNA and protein expression in lung tissue as well as enhanced 3-nitrotyrosine protein expression (P < 0.05 each).

Conclusions

This study describes the time course of pulmonary microvascular hyperpermeability in a clinical relevant large animal model and may improve the experimental design of future studies.     

Vascular endothelial growth factor as an age-dependent prognostic factor in gastric cancer patients

BACKGROUND: We investigated whether vascular endothelial growth factor (VEGF) plays an important role in maintaining constant tumor growth in wasted elderly patients, in whom oxygen and glucose supply are often unable to meet the demands of the body. METHODS: Tissue concentrations of VEGF in 70 gastric carcinomas and 70 normal mucosas were determined. The expression of VEGF was evaluated immunohistochemically. RESULTS: The net balance between the concentration of VEGF in the cancer and normal mucosa (VEGF Ca/N ratio: the cancer tissue VEGF concentration divided by normal mucosa VEGF concentration) increased with age and was associated with disease progression only in elderly patients. VEGF Ca/N ratio increased in response to systemic hypo-oxygenation and nutritional depletion only in elderly patients. CONCLUSIONS: The systemic-local regulating mechanism of VEGF production may play an important role in the constant growth of tumor cells, especially in elderly gastric cancer patients.     

血管内皮生长因子在甲状腺癌的表达及意义

血管内皮生长因子特异性作用于血管内皮细胞,通过促进内皮细胞的增生,增加血管通透性,以诱导肿瘤血管及淋巴管生成,在肿瘤的发生发展中起到关键作用.研究表明,VEGF及其受体的表达与甲状腺癌的发生,淋巴结转移,预后密切相关,抑制VEGF及其受体的表达在甲状腺未分化癌及髓样癌的治疗中有一定的应用前景.     

Vascular endothelial growth factor in chronic rat allograft nephropathy

BACKGROUND: Chronic allograft nephropathy (CAN) is a complex process of alloimmune responses and chronic inflammation leading to fibrosis and vasculopathy. We examined the biological role of proinflammatory vascular endothelial growth factor (VEGF) in a rat renal transplantation model of CAN. METHODS: Syngraft and allograft recipients were treated with a suboptimal dose of cyclosporine A which allows acute rejection and CAN to develop. Intragraft VEGF, VEGFR-1 and VEGFR-2 expressions were determined at 5, 14, 30 and 60 days. Protein tyrosine kinase inhibitor PTK787 was used to inhibit VEGFR activity. RESULTS: In nontransplanted kidneys and syngrafts, mild VEGF expression was observed in the glomeruli and tubuli. VEGFR-1 was detected in vascular structures and VEGFR-2 in glomeruli as well. In allografts, total intragraft VEGF expression and interstitial inflammatory cell VEGF expression were induced and correlated with the chronic allograft damage index (CADI) score. Total intragraft and interstitial inflammatory cell VEGFR-1 expression was induced and interstitial cell VEGFR-1 expression correlated with the CADI score. Blocking VEGF receptor signaling with PTK787 significantly reduced fibrosis and the CADI score, but did not affect early inflammation or VEGF, VEGFR-1, VEGFR-2 expressions compared to vehicle treated group. CONCLUSIONS: Interstitial inflammatory cell VEGF and VEGFR-1 expressions are induced during the development of CAN. Increased VEGF activity may enhance the alloimmune induced inflammatory responses leading to fibrosis and CAN.     

血管内皮生长因子改善大鼠肝移植术后肝功能

目的 探讨血管内皮生长因子(vascular endothelial growth factor, VEGF)对大鼠部分肝移植术后肝功能的影响.方法 建立大鼠30%肝移植模型.分实验组、对照组,每组60只,分别于术后注射鼠重组VEGF、生理盐水.在术后0、12、24、72、168h监测血清ALT、AST、透明质酸(hyaluronic acid, HA)变化.光镜下观察肝窦结构破坏及炎性细胞浸润程度.结果 在72h,实验组血清ALT、AST、HA较对照组明显降低(t=4.681,4.252,2.853,P<0.05).实验组肝窦内皮细胞结构破坏及炎性细胞浸润程度均较对照组明显减轻.结论 VEGF能明显改善大鼠部分肝移植术后肝功能.这可能与其减轻肝窦内皮细胞损害和炎性细胞浸润程度有关.     

糖尿病足动脉缺血患者骨骼肌血管内皮生长因子基因表达

目的　研究糖尿病患者缺血下肢肌肉组织内源性血管内皮生长因子 (VEGF)基因表达及其与糖尿病足发病机理的关系。　方法　将 2 4例患者 ,33条肢体分为 3组 :无下肢动脉缺血的糖尿病 (DM) 5例 ,10条肢体 ;无糖尿病的下肢动脉粥样硬化闭塞症 (ASO) 10例 ,13条肢体 ;糖尿病下肢动脉硬化闭塞症 (DLASO) 9例 ,10条肢体。对照组为正常志愿者 (NOR) 5例 ,10条肢体。通过肌肉穿刺获取小腿骨骼肌组织 ,采用RT PCR法测定肌肉组织中hVEGF16 5mRNA表达。　结果　DM组和NOR组小腿骨骼肌组织中hVEGF16 5mRNA无表达。DLASO组小腿骨骼肌组织有hVEGF16 5mRNA表达 (0 0 2 1± 0 0 13) μg ,但明显低于ASO组 (0 133± 0 0 2 4 ) μg ,(t=13 32P <0 0 1)。　 结论　DLASO组缺血下肢肌组织内源性VEGF基因表达水平明显低于ASO组 ,是糖尿病足部溃疡发生发展的重要内在原因。     

骨肉瘤肺转移与血管内皮生长因子和微血管密度的关系

目的 探讨骨肉瘤盱市转移与血管内皮生长因子(VEGF)和微血管密度(MVD)的关系.方法 用免疫组织化学法检测30例骨肉瘤组织中VEGF的表达和MVD.结果 VEGF在骨肉瘤中的阳性率表达分别为70.00%(21/30),其中有肺转移的病例阳性率为92.31%(12/13).无肺转移病例的阳性率为52.94%(9/17),差异有统计学意义(P<0:05).骨肉瘤组织中VEGF阳性表达与骨肉瘤的组织学分型无明显相关(P>0.05).骨肉瘤中VEGF表达强度与MVD呈正相关(r=0.799,P<0.01);有肺转移的骨肉瘤患者其瘤组织中MVD与无肺转移的骨肉瘤患者其瘤组织中MVD差异有统计学意义(P<0.05),有肺转移的明显高于无肺转移的病例.结论 VEGF是促进微血管生成的主要细胞因子,检测VEGF表达与MVD值可作为判断肿瘤预后的重要指标.     

血管内皮生长因子与治疗性血管生成研究进展

血管内皮生长因子(vascular endothelial growtll factor,VEGF)是内皮细胞特异的有丝分裂原,有促进内皮细胞增生、增强血管通透性、加速新血管形成的作用.血管生成是一个具有重要生理、病理意义的过程.在人体的创伤愈合、炎症反应、器官再生过程以及肿瘤生长转移、血管增生性疾病中,血管生成有重要作用.治疗性血管生成是指利用成血管诱导因子或内皮祖细胞,模拟体内血管生成机制,促进新生血管形成,改善侧支循环.本文就VEGF和治疗性血管生成研究进展做一综述.     

血管内皮生长因子促进预构皮瓣成活的实验研究

目的　研究使用重组人类血管内皮生长因子 (Vascularendothelialgrowthfactor,VEGF)对预构皮瓣存活的作用 ,探讨VEGF能否促进正常血供组织的血管化。方法　取大鼠自体尾动脉 8cm移植 ,两端分别与股动、静脉吻合 ,成环状植入下腹部皮下组织 ,对照组局部应用 0 9%NaCl和16 %聚乙烯乙醇 ,实验组将VEGF分别溶于 0 9%NaCl和 16 %聚乙烯乙醇局部应用。分别于术后 3,4 ,5周以植入的尾动脉为血管蒂于下腹部形成 3cm× 4cm大小皮瓣 ,游离掀起皮瓣后缝回原处 ,7d后运用面积仪测出存活皮瓣面积的百分比。结果　第 5周后的皮瓣存活率VEGF组 (75 0 0 % ,5 8 4 1% )明显优于实验组 (10 % ,2 5 % )。结论　VEGF有利于预构皮瓣的存活。     

乳腺癌组织中血管内皮生长因子mRNA的表达和微血管计数与淋巴结转移的关系

目的：探讨乳腺癌组织中血管内皮生长因子（VEGF）mRNA的表达，微血管密度（MVD）与淋巴结转移的关系。方法：采用逆转录－聚合酶链反应（RT－PCR）和免疫组织化学链霉卵白素－过氧化物酶（SP）法技术，对47例乳腺癌组织VEGF mRNA、VEGF蛋白的表达及微血管密度进行研究。结果：乳腺癌组织VEGF mRNA的表达高于癌旁组织（55．30％：17．02％）。VEGF mRNA的表达与淋巴结转移呈正相关趋势。VEGF表达和MVD与乳腺癌淋巴结转移密切相关（P＜0．05）。癌组织MVD值明显高于癌旁组织MVD值。结论：VEGF与乳腺癌血管生成密切相关，VEGF和MVD表达增高对乳腺癌淋巴结转移有促进作用。     

血管内皮生长因子D促进胃癌淋巴管生长

目的研究血管内皮生长因子D（VEGF-D）与胃癌淋巴管转移之间的关系。方法采用反转录-聚合酶链反应（RT-PCR）从人胃癌旁正常组织中扩增人VEGF-D全长cDNA，经T-A克隆酶切鉴定及测序得到完整的序列后，亚克隆并构建pEGFP／VEGF-D真核表达载体，转染低表达VEGF-D的胃癌细胞株SGC7901，通过体外G418抗生素筛选得到高表达VEGF-D的肿瘤细胞克隆，用这种高表达VEGF-D的胃癌细胞接种于裸鼠皮下，用淋巴管内皮细胞透明质酸盐受体（LYVE-1）行免疫组织化学染色观察肿瘤淋巴管密度和形态。结果对照组和转染pEGFP／VEGF-D组肿瘤的重量分别为（1．13±0．40）g和（2．24±0．82）g，两组差异有统计学意义（P〈0．05）。肿瘤组织内的淋巴管密度分别为2．89±1．32和5．74±1．30，两组差异有统计学意义（P〈0．01）。周边肿瘤组织存在扩张的功能性淋巴管。结论VEGF-D在胃癌中可能通过主动促进淋巴管生长来促进肿瘤生长和远处转移。     

VEGF抗体抑制磨损颗粒诱导骨溶解的实验研究

目的通过观察局部注射VEGF及VEGF抗体对小鼠植骨气囊模型中磨损颗粒诱导骨溶解的影响,探讨VEGF在人工关节无菌性松动中的作用。方法取人工髋关节翻修术取出的金属关节假体柄,参照真空球磨法体外制备磨损颗粒,PBS配制成浓度为10 mg/mL颗粒悬液。取8～10周龄雌性昆明小鼠50只,体重约25 g。10只作为气囊植骨模型颅骨供体。剩余40只小鼠随机分为4组(n=10),分别为空白对照组(A组)、颗粒组(B组)、VEGF刺激组(C组)和VEGF抑制组(D组);小鼠背部皮下注射无菌空气制备气囊,第8天切开气囊植入颅骨骨片,制备植骨气囊模型。于植骨后第1天B、C、D组气囊内注入0.5 mL颗粒悬液,A组注入0.5 mL PBS。气囊制备期间第6、7天及植骨后隔天,C、D组气囊内分别注射0.2 mL重组人VEGF和Bevacizumab溶液,A、B组注射0.2 mL生理盐水。植骨2周后取囊壁连同骨片行HE染色、实时荧光定量PCR及ELISA检测。结果各组小鼠均存活至实验完成。大体观察见A组气囊红肿程度轻,新生血管少;B、C、D组气囊明显红肿,可见较多渗出及新生血管,其中C组最重,B组次之,D组介于A、B组间。组织学及分子生物学检测发现,B组囊壁明显炎性反应及骨溶解,囊壁厚度、细胞密度及TNF-α、IL-1β、VEGF表达均较A组明显增加(P<0.05);C组囊壁炎性反应及骨溶解最显著,以上观察指标均高于B组(P<0.05);D组囊壁亦可见炎性反应及骨溶解,但以上指标均低于B组(P<0.05),高于A组(P<0.05)。结论 VEGF在人工关节无菌性松动中具有促进炎性反应及骨溶解作用,局部给予VEGF抗体可抑制磨损颗粒诱导的骨溶解。     

Vascular endothelial growth factor promotes peripheral nerve regeneration after sciatic nerve transection in rat

Objective：To evaluate the local effect of vascular endothelial growth factor （VEGF） on transected sciatic nerve regeneration.Methods：Sixty male white Wistar rats were divided into four experimental groups randomly （n=15）.In transected group the left sciatic nerve was transected and the stump was fixed to adjacent muscle.In treatment group the defect was bridged using a silicone graft filled with 10μL VEGF.In silicone group the graft was filled with phosphate-buffered saline.In sham-operated group the sciatic nerve was exposed and manipulated.Each group was subdivided into three subgroups with five animals in each and nerve fibers were studied 4,8 and 12 weeks after operation.Results：Behavioral test,functional study of sciatic nerve,gastrocnemius muscle mass and morphometric indices confirmed a faster recovery of regenerated axons in VEGF group than in silicone group （P〈0.05）.In immunohistochemical assessment,reactions to S-100 in VEGF group were more positive than that in silicone group.Conclusion：Local administration of VEGF will improve functional recovery and morphometric indices of sciatic nerve.     

血管内皮生长因子在脑胶质瘤中自分泌研究

目的 观察血管内皮生长因子(VEGF)在脑胶质瘤中自分泌现象.方法 采用免疫组织化学及图像分析方法 ,检测74例脑胶质瘤中肿瘤细胞上血管内皮生长因子受体VEGFR1和VEGFR2的表达,取其中42例检测VEGF的表达的情况.结果 VEGF在胶质瘤中表达强度与肿瘤病理级别明显相关(P＜0.05,r=0.331);VEGFR1、2在胶质瘤瘤细胞中表达强度吸光值分别为:正常组织(0.2104±0.0297)和(0.2100±0.0257);WHO I(0.2328±0.0194)和(0.2324±0.0186);WHOⅡ级(0.2533±0.0155)和(0.2514±0.0147);WHO Ⅲ级(0.2709±0.0203)和(0.2720±0.0149);WHOⅣ级(0.2906±0.0282)和(0.2834±0.0285);表达强度与胶质瘤病理级别明显相关(P＜0.01,r=0.748;P＜0.01,r=0.754).结论 在脑胶质瘤中存在VEGF的旁分泌和自分泌现象,并与病理级别有关.     

Vascular endothelial growth factor and bladder from a different perspective: not only an angiogenic factor

Angiogenesis has a key role for embryonic development and is crucial in several major diseases. Molecular basis of angiogenesis has been widely investigated (J Biochem Mol Biol. 2006;39:469-478, Oncogene. 2000;19:5598-5605). In this review, vascular endothelial growth factor (VEGF) and related receptors and their key roles in embryonic bladder development are discussed. The normal VEGF expression and related angiogenesis pattern of embryonic bladder are highlighted. The VEGF family especially VEGF-A is the major player in angiogenesis as well as many other angiogenic factors and activates 2 tyrosine kinase receptors, VEGFR-1 and VEGFR-2 (J Biochem Mol Biol. 2006;39:469-478). Besides its worthy role in angiogenesis, VEGF-A also seems to participate in normal bladder development (J Urol. 2007;177:1552-1557, Br J Urol Int. 2006;98:217-225). In previous studies, we have shown that exogenous VEGF or hypoxia-induced endogenous upregulation of this protein accelerates the growth of the bladder by detrusor and urothelium hypertrophy and hyperplasia (J Urol. 2007;177:1552-1557, Br J Urol Int. 2006;98:217-225, Dev Biol. 1997;183:139-149, Neurourol Urodyn. 2004;23:342-348). This abrupt role of VEGF on detrusor muscle through a hypoxic pathway may potentially be a part of the solution for many urologic conditions such as remodeling of detrusor muscle in antenatal bladder outlet obstruction.     

血管内皮生长因子在宫颈癌组织中的表达

目的探讨血管内皮生长因子(VEGF)在宫颈癌组织中的表达,及其与病理分化、临床分期和盆腔淋巴结转移的关系。方法用免疫组织化学法检测52例宫颈癌和14例正常宫颈组织VEGF的表达。结果VEGF在宫颈癌组织阳性表达率为56%,在正常宫颈组织为0,两种组织间比较差异有统计学意义(P<0.05);VEGF与宫颈癌临床分期和盆腔淋巴结转移呈显著相关。结论VEGF在宫颈癌组织的表达与肿瘤的浸润、转移及预后密切相关。     

肌腱愈合早期血管内皮生长因子及其受体的表达

目的 :探讨血管内皮生长因子在肌腱愈合早期的表达规律及其受体在修复区血管内皮细胞内的表达类型。方法 :新西兰白兔 12只 ,制作肌腱损伤粘连模型 ,术后随机分为 4、 7、 10、 14d四个时相组 ,每组 3只 ,,按分组于相应时相点取肌腱标本固定 ,利用免疫组织化学技术分别检测VEGF及其受体在修复区的表达情况。结果 :术后4～ 14d的肌腱修复区 ,多种组织细胞参与表达VEGF ,7～ 10d为表达的高峰期 ;在术后 4～ 14d的修复区血管内皮细胞内检测到VEGF受体flt 1和flk 1的表达 ,但两者表达的高峰不一致。结论 :VEGF及其受体flt 1和flk 1在肌腱损伤后的早期表达增高 ,VEGF通过与其受体的特异性结合后可能在肌腱的外源性愈合中发挥重要的调节作用     

Vascular endothelial growth factor trap-eye (Aflibercept) for the management of diabetic macular edema

Diabetic retinopathy (DR) is the most common cause of visual loss among working age individuals. Diabetic macular edema (DME) is an important complication of DR that affects around one third of the patients with DR. Several treatments have been approved for DME ranging from blood pressure and glycemic control to photocoagulation and more recently the use of vascular endothelial growth factor (VEGF) antagonists. The index review discusses aflibercept (EYLEA^®-Regeneron Pharmaceuticals, Inc., Tarrytown, New York, NY, and Bayer Healthcare Pharmaceuticals, Berlin, Germany) in the context of other VEGF antagonists currently available for the treatment of DME. A systematic search of literature was conducted on PubMed, Scopus, and Google Scholar with no limitation on language or year of publication. Pre-clinical studies of aflibercept have shown a higher affinity of this molecule for vascular endothelial growth factor A (VEGF-A) along with a longer duration of action as compared to other VEGF antagonists. Recent clinical trials have shown visual outcome results for aflibercept to be similarly favorable as compared to other available agents with the added benefit of fewer required injections and less frequent monitoring. Aflibercept presents a potential exciting new addition to the armamentarium of current VEGF antagonists available for the treatment of DME and other retinal vascular diseases. However, further studies are indicated to confirm the role, safety, and efficacy of aflibercept for DME.     

血管内皮生长因子:从血管形成到神经元保护

血管内皮生长因子(vascular endotjelial growthfactor,VEGF)是一类多功能的生长因子。它具有促进内皮细胞增殖、诱导血管形成的作用,因而被应用于缺血性血管疾病(如缺血性心肌病和下肢缺血)的治疗,并成为近年来心血管病研究的热点之一。新近研究发现,VEGF及其受体在中枢神经组