血管内皮生长因子在子宫内膜异位症发病中的作用

目的探讨血管内皮生长因子(vascularendothelialgrowthfactor,VEGF)在子宫内膜异位症(endometriosis,EM)发病中的作用。方法应用免疫组织化学方法并结合图像分析技术。结果正常子宫内膜和EM在位内膜腺上皮细胞的VEGF随月经周期呈现规律性变化,分泌期腺上皮VEGF蛋白表达量显著高于增殖期(P<0.05)。在增殖期,EM在位子宫内膜腺上皮VEGF的表达与正常子宫内膜相比无明显差别,但在分泌期,EM在位子宫内膜腺上皮细胞中VEGF的表达强度明显高于正常子宫内膜(P<0.01)。EM在位内膜腺上皮的VEGF含量显著高于同组卵巢子宫内膜异位囊肿的异位腺上皮(P<0.01)。结论表明VEGF的表达异常与EM的发病有关。     

Expression of vascular endothelial growth factor C and anti-angiogenesis therapy in endometriosis

Angiogenesis is an important pathogenesis of Endometriosis. Vascular endothelial growth factor C (VEGF-C) is one of the most important factor in the regulation of both normal and abnormal angiogenesis. Anti-angiogenic treatment of endometriosis is still in the exploratory stage. In this study, we investigate the relationship between VEGF-C and endometriosis, the therapeutic effects of Endostar in the rat endometriosis model. We then demonstrated that Immunohistochemical expression of VEGF-C was higher in endometriotic tissues than in control normal ovary tissues (P < 0.01) and higher in the endomertriosis grade III-IV than in endomertriosis grade I-II (P=0.013). In rat endometriosis model, we observed a significant reduction in the mean volume and weight of the endometriotic implants per rat in the treatment group as compared with the control group. By immunohistochemical evaluation, there was a significant reduction in VEGF-C expression after treatment in all areas examined. VEGF-C may be involved in the pathogenesis of endomertriosis by regulating the angiogenesis. Endostar has therapeutic effects of endometriosis lesions in the rat endometriosis model.     

Vascular endothelial growth factor A and C gene expression in endometriosis

Angiogenesis is essential for the pathogenesis of endometriosis. Gene expression levels of vascular endothelial growth factor (VEGF) A and C in 10 eutopic endometrial, 23 normal peritoneal, and 62 endometriotic tissues surgically obtained from 47 women with endometriosis (group 2) were compared with those in 12 control eutopic endometrial and 9 normal peritoneal tissues from 15 women without endometriosis (group 1). VEGF-A mRNA expression levels in eutopic endometrium of group 2 were higher than those of group 1 throughout the menstrual cycle (P <0.01) and increased in the secretory phase. VEGF-A gene expression in peritoneal endometriotic lesion was statistically higher than that in normal peritoneum (P <0.01) and similar to that in eutopic endometrium of group 2. In contrast, gene expression levels of VEGF-C were relatively lower than those of VEGF-A in each lesion, and no cyclic variation was found. VEGF-A and C mRNA expression levels were significantly higher in ovarian endometriomas >6 cm in size than in those <6 cm in size. Immunohistochemical expression of VEGF-A and C was detected in the cytoplasm of glandular epithelial and stromal cells of ovarian endometrioma. These results suggest that endometriosis may arise from eutopic endometrium with higher levels of angiogenic activity possibly induced by VEGF-A in women with endometriosis. Moreover, VEGF-C as well as VEGF-A may be involved in the pathogenesis of ovarian endometrioma.     

白介素-17和血管内皮生长因子在子宫内膜异位症中的作用

目的:探讨白介素-17(IL-17)和血管内皮生长因子(VEGF)在子宫内膜异位症血管生成中的作用。方法:采用免疫组织化学及免疫印迹方法检测50例异位症患者在位内膜、异位内膜及47例正常子宫内膜组织中IL-17及VEGF蛋白表达。结果:各组内膜组织腺上皮细胞及基质细胞中均有IL-17和VEGF蛋白表达,内膜异位症在位内膜及异位内膜均高于同期对照组内膜,差异均有统计学意义;对照组分泌期内膜IL-17和VEGF蛋白表达均高于增生期,呈周期性变化,而内膜异位症组分泌期与增生期IL-17和VEGF蛋白均呈高表达,失去周期性变化。结论:内膜异位症患者在位及异位内膜组织中IL-17及VEGF蛋白高表达可能与内膜异位症的发生发展有关。     

紫草素对人鼠嵌合内异位症模型血管内皮生长因子表达的影响

目的通过研究紫草素对内异症小鼠模型血管内皮生长因子（VEGF）表达的影响,探究其治疗子宫内膜异位症（EMs）的可能机制。方法建立人鼠嵌合内异症动物模型,随机分为紫草素大、中、小剂量组,另设PBS阴性对照组及达菲林阳性对照组,采用免疫组化法,比较用药前后移植人子宫内膜VEGF表达变化情况。结果各剂量紫草素均抑制VEGF表达,大、中剂量组与阴性对照组相比差异有统计学意义（P〈0.05）,与达菲林组比较无显著性差异（P〉0.05）。结论紫草素可能通过抑制异位内膜血管新生,阻止其种植和生长而治疗EMs。     

Association study of the vascular endothelial growth factor gene with the risk of developing Alzheimer's disease

Numerous observations indicate that cerebrovascular dysfunction contributes to cognitive decline and neurodegeneration in AD. Converging evidence points to a pivotal role for vascular endothelial growth factor (VEGF) in neuronal protection, and the lack of activity of this in neurodegenerative disorders. The VEGF gene is located at 6p21.3, a site several studies have shown to have significant linkage with AD, and a functional polymorphism within the VEGF promoter may alter the risk of developing AD. We assessed the potential impact of this polymorphism on the risk of developing AD in a large French case-control population, and investigated its association with the severity of brain vascular lesions (arteriosclerosis, white matter loss and cerebral amyloid angiopathy) in several brain regions (frontal, temporal, parietal and occipital cortex) in AD. No association of the VEGF promoter polymorphism with the risk of developing AD was observed. No relationship between this polymorphism and vascular pathological changes in AD was detected. Our data indicate that although this polymorphism is functional, it does not confer greater risk for AD, nor modulate the extent of vascular pathology.     

The vascular endothelial growth factor +405G>C polymorphism in endometriosis

BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent stimulus of angiogenesis potentially contributing to the pathogenesis of endometriosis. The aim of this study was to investigate the potential association between the single nucleotide polymorphism +405G>C of the VEGF gene with the risk of endometriosis, for the first time in the Caucasian population. METHODS: The polymorphism +405G>C of the VEGF gene was examined in n = 203 Italian women affected by endometriosis and in n = 140 women without laparoscopic evidence of the disease. All the women were genotyped by PCR-restriction fragment length polymorphism from venous blood samples. We then performed a meta-analysis including results from the present study and from the two previously published studies on this topic. RESULTS: The distribution of the three different genotypes significantly differed between women with and without the disease (P = 0.03). The odds ratio (95% confidence interval) for endometriosis in women carrying the C allele was 1.8 (1.2-2.8). The Breslow-Day test revealed statistically significant heterogeneity among the studies performed so far thus indicating inconsistency among studies and excluding the possibility of obtaining a common estimation of the effect. CONCLUSIONS: Results obtained herein are in keeping with those obtained previously and support a role for the +405G>C VEGF polymorphism in endometriosis development, although a further, larger study is required to confirm our findings. However, this effect may depend on the population studied. Ethnicity and the characteristics of endometriosis are likely to influence this association.     

血管内皮生长因子及其受体在子宫内膜异位症中的表达和意义

目的:研究血管内皮生长因子(Vascular endothelial growth factor,VEGF)及其受体(Vascular endothelial growth factor receptor1,VEGFR1)在子宫内膜异位症(内异症)患者子宫在位内膜、异位内膜及正常对照组内膜组织中的表达,探讨其在子宫内膜异位症中的作用机制.方法:采用免疫组织化学及Western blot方法检测34例异位症患者在位内膜、异位内膜(内异症组)及34例正常内膜(对照组)组织中VEGF及其受体VEGFR1蛋白的定位及表达.结果:异症组在位及异位子宫内膜组织腺上皮细胞及间质细胞中均有VEGF及VEGFR1蛋白表达,且均高于同期对照组内膜,差异有统计学意义;对照组分泌期内膜VEGF及VEGFR1蛋白表达高于增生期,呈现周期性变化,而内异症组在位及异位内膜VEGF及VEGFR1蛋白表达失去周期性变化,分泌期与增生期均高表达,差异无统计学意义.Western blot检测结果与免疫组化结果一致.结论:内异症患者在位及异位内膜组织中VEGF、VEGFR1蛋白高表达可能与内异症的发生发展有关.     

Analysis of vascular endothelial growth factor gene 936 C/T polymorphism in patients with familial Mediterranean fever

Vascular endothelial growth factor (VEGF) is a cytokine that promotes endothelial cell proliferation, leucocyte chemotaxis and expression of adhesion molecules and is a major mediator of vascular permeability. It has been demonstrated that VEGF directly activates neutrophils and it could promote acute recruitment of leucocytes. It is known that neutrophils are the major cell population involved in acute inflammation in familial Mediterranean fever (FMF) and the role of VEGF in these cells may be crucial. The aim of this study was to investigate whether the 936 C/T functional polymorphism of the VEGF gene is associated with susceptibility to FMF and its relationship with the main clinical features of the disease. Polymerase chain reaction-restriction fragment length polymorphism technique was used to determine 936 C/T polymorphism within the VEGF gene in 75 patients with FMF and 122 non-related healthy controls. Genotype and allele frequencies of the VEGF 936 C/T polymorphism between patients with FMF and healthy control groups were not significantly different (OR = 0.74, 95% CI = 0.40-1.37, P = 0.335 for CT genotype; OR = 1.11, 95% CI = 0.67-1.83, P = 0.700, for T allele). Although VEGF 936 TT genotype was found to be more frequent in patients with FMF than in healthy controls (6.7% vs. 1.6%, respectively), the difference was not significant (OR = 4.28, 95% CI = 0.81-22.67, P = 0.108). No associations were found between the studied polymorphism and either the clinical features such as arthritis, abdominal pain, pleuritis, myalgia, arthralgia and erysipelas-like erythema of the disease or the four common studied exon 10 mutations (M694V, M680I, V726A, M694I) of the Mediterranean fever gene. Present results suggest that VEGF gene 936 C/T polymorphism does not seem to be associated with susceptibility to FMF and its clinical manifestations.     

Levels of vascular endothelial growth factor (VEGF) in serum of patients with endometriosis

BACKGROUND: Elevated concentrations of vascular endothelial growth factor (VEGF) have been detected in the peritoneal fluid of patients with endometriosis. Furthermore, it was postulated that VEGF is involved in the development of endometriotic lesions. The present study is aimed at determining whether high levels of VEGF could also be found in the serum of patients with endometriosis. METHODS: VEGF levels were measured by enzyme-linked immunosorbent assay (ELISA) in serum from 131 subjects with surgically confirmed endometriosis and 146 controls with no clinical evidence of the disease or detectable endometriotic lesions at the time of surgical examination. Parameters such as demographics, personal habits, menstrual characteristics and clinical profile were collected from each subject included in this study. RESULTS: The mean VEGF levels were not significantly modulated in serum samples of cases compared with controls in a crude general linear model and in a model adjusted for possible confounders. VEGF serum levels did not correlate with the score, stage of endometriosis or the presence of benign gynaecological disorders. However, a correlation was found between circulating concentrations of VEGF and body mass index. CONCLUSION: Although VEGF seems to play a pivotal role locally in the implantation and development of endometriotic lesions, the disease is not associated with a significant modulation in the levels of circulating VEGF.     

COX-2、VEGF以及MVD在子宫内膜异位症中的表达及意义

目的通过探讨环氧合酶-2（COX-2）、血管内皮生长因子（VEGF）以及微血管密度（MVD）在子宫内膜异位症（EMs）在位内膜、异位内膜及正常子宫内膜组织中的表达,探讨子宫内膜异位症的发病机制。方法采用免疫组化SP法检测EMs患者32例在位内膜、28例异位内膜及40例对照组正常子宫内膜中COX-2、VEGF的蛋白表达,计数微血管密度（MVD）值,并进行相关性分析。结果 （1）COX-2、VEGF在EMs在位内膜、异位内膜阳性表达率明显高于正常对照组,差异具有统计学意义（P〈0.05）,EMs异位内膜组COX-2、VEGF阳性表达率高于在位内膜组,差异有统计学意义（P〈0.05）。（2）MVD的计数在正常对照组,在位内膜组,异位内膜组依次递增,在位内膜组、异位内膜组与正常对照组比较有统计学差异（P〈0.05）,而在位内膜组与异位内膜组比较有统计学差异（P〈0.05）。（3）EMs在位内膜、异位内膜组患者和正常对照组COX-2蛋白表达与VEGF蛋白及MVD值的变化呈正相关。结论 COX-2与VEGF在EMs中的高表达,与子宫内膜异位的血管生成有关。     

Steroid-sensitive nephrotic syndrome and vascular endothelial growth factor gene polymorphisms.

Genetic polymorphisms have been recognized as important determinants of gene expression. Three common single nucleotide polymorphisms have been identified in the promoter and 5' untranslated region of the vascular endothelial growth factor (VEGF) gene: -460 C --> T, -141 A --> C and +405 G --> C. As VEGF has been postulated to play a role in the pathogenesis of childhood steroid-sensitive nephrotic syndrome (SSNS), this study tested the hypothesis that VEGF genotype may be associated with susceptibility to SSNS. We examined the genotype frequencies of these polymorphisms in a total of 116 children with SSNS and 150 control subjects, using polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). There were no statistically significant differences in any of the genotype frequencies between SSNS patients and controls. We conclude that VEGF -460, -141 and +405 genotypes are not associated with susceptibility to childhood SSNS.     

Lung overexpression of the vascular endothelial growth factor gene induces pulmonary edema

We hypothesized that the angiogenic mediator, vascular endothelial growth factor (VEGF), known to be expressed in the lung and to be capable of inducing local edema in skin, might evoke the development of lung edema if expressed in excess amounts. To test this hypothesis, we developed an in vivo model of VEGF overexpression in the lung on the basis of delivery to the respiratory epithelium of the VEGF165 complementary DNA by an E1(-) adenovirus vector (AdVEGF165). Administration of AdVEGF165 by the intratracheal route (10(9) plaque-forming units [pfu]) to C57Bl/6 mice showed increased expression of VEGF messenger RNA in lung tissue by Northern analysis. Overexpression of VEGF protein in the lung at Days 1 to 10 was confirmed by enzyme-linked immunosorbent assay. Intratracheal administration of AdVEGF165 resulted in a dose-dependent increase in lung wet/dry weight ratios over time, lung histology showed widespread intra- alveolar edema, and pulmonary capillary permeability was significantly increased as quantified by the Evans blue dye assay and [(131)I]albumin permeability. To confirm the specificity of these observations, mice were pretreated with intranasal administration of an adenovirus vector expressing a truncated soluble form of the VEGF receptor flt-1 (Adsflt). Adsflt (10(9) pfu) pretreatment completely abrogated the increased lung wet/dry weight ratio caused by AdVEGF165 administration, whereas an identical adenovirus vector with an irrelevant transgene had no effect upon subsequent AdVEGF165-induced pulmonary edema. Together, these data suggest that overexpression of VEGF in the lung may be one mechanism of increased pulmonary vascular permeability in the early stages of acute lung injury.     

血管内皮生长因子的免疫学测定法

目的：检测肿瘤细胞条件培养液中ＶＥＧＦ的表达量。方法：在表达及分离纯化ＶＥＧＦ的基础上,成功地制备了ＶＥＧＦ抗体,以夹心法测定ＶＥＧＦ,ＶＥＧＦ测定范围为０．０２～２００．００ｎｇ／ｍｌ,灵敏度可达０．０２ｎｇ／ｍｌ,批内及批间变异均小于１０％,回收率平均为１０２．４％。其中人胃癌细胞ＭＧＣ８０３、ＢＧＣ８２３、乳癌ＮＭＣＦ－７及肝癌ＢＥＬ－７４０２分泌上清中ＶＥＧＦ的含量分别为６．５０、０．４５     

Vascular endothelial growth factor (VEGF) in endometriosis

Angiogenesis is likely to be involved in the pathogenesis of endometriosis. According to the transplantation theory, when the exfoliated endometrium is attached to the peritoneal layer, the establishment of a new blood supply is essential for the survival of the endometrial implant and development of endometriosis. From the known angiogenic factors, vascular endothelial growth factor (VEGF) has emerged as a pivotally important regulator of normal angiogenesis and pathological neovascularization. The VEGF protein was evaluated immunohistochemically in the eutopic endometrium of 10 women without endometriosis (group I) at laparoscopy and the eutopic endometrium and peritoneal endometriotic lesions of 43 women with endometriosis (group II). VEGF histological scores were 9.7 +/- 4.3 and 4.0 +/- 2.6 respectively in the epithelium and stroma of the eutopic endometrium of group I women, and 10.3 +/- 2.3 and 3.6 +/- 2.3 respectively in women of group II. In red lesions, the VEGF scores were 11.1 +/- 3.0 in the epithelium and 5.1 +/- 3.0 in the stroma, and in black lesions were 8.6 +/- 2.7 and 1.6 +/- 1.6, respectively. Significantly lower values were observed in black lesions as compared with eutopic endometrium and red lesions, the values of which were similar. Scores were also evaluated according to the phase of the cycle. In eutopic as well as ectopic endometrium, no significant cyclic variations were observed throughout the cycle. However, VEGF content was found to be higher in the eutopic glandular epithelium of women with endometriosis during the late secretory phase, possibly suggesting a more likely tendency to implant. In contrast, significantly higher VEGF content was noted in red lesions as compared with black lesions. During all phases of the cycle, the VEGF content in stromal cells of red lesions was higher than in black lesions. Similarities in VEGF content were observed in the glandular epithelium of the eutopic endometrium of women with endometriosis and red lesions, suggesting that endometriosis probably arises from the peritoneal seeding of viable endometrial cells during retrograde menstruation and that red lesions can be considered as the first stage of implantation. After the attachment phase, the high VEGF levels could provoke an increase in the subperitoneal vascular network and facilitate implantation and viability in the retroperitoneal space. Lower VEGF levels in black lesions explain the decrease in both stromal vascularization, followed by fibrosis and inactivation of the implant.      

Changes in circulating levels of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 after carotid endarterectomy

It has been shown that vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) are upregulated in severe carotid stenosis. However, it is unknown whether carotid endarterectomy (CEA) affects serum level of these molecules. We investigated changes in concentration of VEGF and VEGFR-2 in patients undergoing carotid endarterectomy. Forty-three patients with extracranial carotid stenosis (>70%), were studied. Patients with severe vertebrobasilar stenosis, recent (<1 month) vascular event (stroke, coronary infarction, arterial thromboembolism), critical ischemia of lower extremity, recent infection, autoimmune disease or malignancy were excluded from the study. Blood samples were taken before CEA and on the second post-operative day. Thirty healthy blood donors served as a control group. We used enzyme linked immuno-absorbent assay as a method for the determination of VEGF and VEGFR-2. Pre-operative levels of VEGF (371+/-42 pg/ml) and VEGFR-2 (8424+/-356 pg/ml) were significantly elevated. There was significant decrease in both VEGF (152 pg/ml) and VEGFR-2 (1297 pg/ml) after CEA, without however reaching normal values. In asymptomatic patients and in patients with a contralateral carotid stenosis of >50%, however, the observed reduction of VEGF did not reach statistical significance. On the other hand, in the same subgroups, a major decrease of VEGFR-2 values was observed. VEGF and VEGFR-2 showed a very significant increase in serum of patients with severe carotid stenosis. These pre-operative levels decreased significantly after endarterectomy, and the changes emphasize the importance of these molecules in carotid disease progression.     

Hypoxia and cobalt stimulate vascular endothelial growth factor receptor gene expression in rats

 This study aimed to examine the influence of acute tissue hypo-oxygenation on the expression of the vascular endothelial growth factor (VEGF) receptor genes. To this end male Sprague-Dawley rats were exposed to different hypoxic conditions such as 10% or 8% oxygen, 0.1% carbon monoxide and cobalt chloride (60 mg/kg) for 6 h and the abundance of flt-1, flt-4 and flk-1 mRNA in lungs and livers was determined by RNase protection assay. The relative proportions of flt-1, flt-4 and flk-1 were 10 : 2.5 : 1 and 10 : 10 : 2 in normoxic lungs and livers, respectively. It was found that 8% but not 10% oxygen increased flt-1 mRNA two- to threefold in both organs, whilst flt-4 and flk-1 mRNA were not changed by acute inspiratory hypoxia. Carbon monoxide inhalation also increased flt-1 mRNA but not flt-4 or flk-1 mRNA in both organs. Subcutaneous cobalt administration increased flt-1 mRNA in the livers only, whilst flt-4 and flk-1 mRNA remained unchanged. These findings show that acute tissue hypo-oxygenation is a rather selective stimulus for flt-1 gene expression. The efficiency of the different manoeuvres applied to stimulate flt-1 gene expression is rather similar to the stimulation of erythropoietin gene expression. It is not unreasonable to assume, therefore, that the oxygen-dependent regulation of both genes at the cellular level has significant similarities.     

脂质体介导的VEGF基因对培养血管细胞增殖的影响

目的：观察脂质体介导转移的VEGF基因在血管平滑肌细胞（VSMC）中的表达，比较VEG对血管内皮细胞（VEC）及VSMC增殖的影响。方法：将含血管内皮生长因子（VECF）CDNA的真核表达载体pSV121用脂质体介导的基因转移法导入血管平滑肌细胞（VSMC）中，取此VSMC条件培养液，再行血管内皮细胞（VEC）培养，用Northmblot杂交，Westem印迹法及[~3H]胸腺嘧啶核苷掺入法，观察了VEGF在VSMC及其条件培养液中的表达，比较了VEGF对VEC及VSMC增殖的影响。结果：转基因组VSMC中VEGFmRNA呈稳定高表达，转基因组VSMC条件培养液中，VEGF抗原表达显著高于对照组（P均＜0．01），加入此条件培养液的各组VEC的[~3H]胸腺嘧啶核苷掺入量均显著高于对照组（p均＜0．01），而在VSMC组无显著差异。结论：VEGF的转录和表达表明脂质体介导的血管细胞VEGF基因转移是成功的。VEGF具有促VEC增殖作用，但对VSMC无促增殖作用，有利于缺血性疾病及血管再狭窄的防治。     

血管内皮生长因子基因多态性与反复自然流产

血管内皮生长因子(VEGF)是一种具有多种生物学效应的多功能细胞因子,在正常妊娠中发挥重要的作用,其表达水平异常将导致病理性妊娠的发生。VEGF基因多态性可导致VEGF表达量的变化,从而影响妊娠过程中血管的生成和浸润,诱发反复自然流产。本文就血管内皮生长因子基因多态性与反复自然流产的相关性作以综述。     

Hepatocyte growth factor increases expression of vascular endothelial growth factor and plasminogen activator inhibitor-1 in human keratinocytes and the vascular endothelial growth factor receptor flk-1 in human endothelial cells

The pleiotropic growth factor hepatocyte growth factor/scatter factor (HGF/SF) has been implicated by clinical and experimental studies in repair mechanisms in different organs and tissues. However, no data on the impact of HGF/SF in wound healing in the skin are yet available. Proliferating and migrating keratinocytes play a major role in repair processes in the skin by closing the wound. Recent evidence gathered from studies that used gene-deficient mice has implicated the plasminogen activator (PA)/plasmin system in wound healing, which depends on controlled matrix degradation and deposition during cell migration and proliferation. Furthermore, keratinocytes are an important source of vascular endothelial growth factor (VEGF), which is a potent inducer of angiogenesis. In this study, we show that in human keratinocytes HGF/SF but not the related cytokine macrophage stimulating protein (MSP) significantly increases expression of VEGF and plasminogen activator inhibitor-1 (PAI-1) on the level of protein and mRNA. Furthermore, we demonstrate that HGF/SF increases the expression of the VEGF receptor flk-1 in human endothelial cells and that, in an angiogenesis co-culture assay of endothelial cells and keratinocytes, HGF/SF increases endothelial cell tube formation significantly. Therefore, we propose a role for HGF/SF in wound repair in the skin: HGF/SF--produced by activated fibroblasts--increases in keratinocytes the expression of PAI-1, which leads to increased matrix stability during the repair process and which could also limit activation of HGF/SF by proteases such as urokinase-type PA (u-PA) or tissue-type PA (t-PA). Furthermore HGF/SF also increases the expression of VEGF in these cells, thereby initiating angiogenesis in a paracrine manner. This effect would be enhanced by an increased responsiveness of endothelial cells toward VEGF, resulting from the HGF/SF-induced up-regulation of flk-1 on these cells.