血管内皮生长因子研究进展

血管内皮生长因子（ＶＥＧＦ）是一种能特异地作用于血管内皮细胞的生长因子。在生理和病理情况下均有表达本文就ＶＥＧＦ的分子特征,ＶＥＧＦ受体及信号传导机制,表达调节和生物学特征作一综述。     

血管内皮生长因子与血管生成

本综述了血管内皮生长因子结构特点、体内分布,正常及病理条件下的表达水平变化及其生物学功能,并对血管通透性与血管生成之间的关系进行了评述。     

血管内皮生长因子

血管内皮生长因子叶正茂,周爱儒（北京医科大学生化与分子生物学系,北京１０００８３）关键词血管内皮生长因子,血管通透因子,血管生成血管内皮生长因子（ＶＥＧＦ,ｖａｓｃｕｌａｒｅｎｄｏｔｈｅｌｉａｌｇｒｏｗｔｈｆａｃｔｏｒ）又称血管通透因子（ｖａｓｃｕｌ...     

血管内皮生长因子家族及其受体与肿瘤血管生成研究进展

血管内皮生长因子(vascular endothelial growth factor,VEGF),又名血管通透性因子(vascular permeability factor,VPF)是重要的血管生成正性调节因子,是目前抗癌治疗的研究靶点之一。现已发现的VEGF家族成员包括VEGF—A、VEGF—B、VEGF—C、VEGF—D、VEGF—E和胎盘生长因子(placenta growth factor,PLGF)。VEGF的受体有VEGFR—1(fit—1)、VEGFR-2(flk-1／KDR)、VEGFR-3(fit-4)、neuropilin(NPR1／NPR2)。该家族的成员可以选择性地增强血管和／或淋巴管内皮细胞的有丝分裂,刺激内皮细胞增殖并促进血管生成,提高血管特别是微小血管的通透性,使血浆大分子外渗沉积在血管外的基质中,促进新生毛细血管网的建立,为肿瘤细胞的生长提供营养等。作者对VEGF家族成员及其受体的理化特征、VEGF与肿瘤的关系、VEGF抑制剂的研制作一综述。     

血管内皮生长因子受体--结构与功能

血管内皮生长因子 (VEGF)的生物学效应是通过其特异的膜受体介导实现的。迄今发现VEGF有三种受体 ,受体的结构、功能 ,及VEGF的信号转导途径各不相同 ,也一直是VEGF研究的热点。本文主要综述了这方面的进展。     

胰岛素受体及其底物与血管内皮生长因子

VEGF参与肿瘤发生与发展、缺血性血管病变、糖尿病小血管异常增生等多个病理生理过程,胰岛素受体及其底物作为VEGF的调节因素之一可通过多种途径影响VEGF的表达。文章综述了在糖尿病视网膜病变、肿瘤、缺血性血管病等不同病理生理条件下胰岛素受体及其底物对VEGF表达的影响,推测两者之间可能存在的调节机制。     

血管内皮生长因子的功能与应用

血管内皮生长因子是特异作用于血管内皮细胞的一类糖蛋白,以同源二聚体的形成存在,具有强烈的促内皮细胞增殖作用,促进新血管的形成,在血管再狭窄,冠脉缺血和肢体缺血等疾病中,通过加强ＶＥＧＦ的正性治疗作用,达到治疗的目的。而在视网膜新血管形成,类风湿关节炎和肿瘤等疾病时,则通过抑制ＶＥＧＦ的负性治疗作用,减少新血管形成,抑制疾病的发展。     

血管内皮生长因子与肺癌治疗

肺癌是世界上主要癌症杀手之一,大部分肺癌病人都死于肿瘤转移所引起的并发症.由于现在大部分的肺癌病人预后不佳,因此寻找新方法、新途径治疗尤为重要.抗血管生成是目前的肿瘤治疗研究热点之一.对目前以抗血管内皮生成因子为手段的肺癌治疗方面的研究作一综述.     

血管内皮生长因子受体的结构与功能

血管内皮生长因子(VEGF)受体是存在于血管内皮细胞,介导内皮细胞增殖分化的跨膜受体.研究较多的有两种VEGF特异受体:Flt和KDR.Flt和KDR的基因结构及染色体定位已基本确定,这二者均属RTK Ⅲ型受体,结构相似.细胞外区均有7个类似免疫球蛋白结构,细胞内区催化域均有酪氨酸激酶插入区.当VEGF与受体结合时,引起受体自身的磷酸化,发生细胞内反应.在血管发生与生长、创伤修复、炎症、肿瘤和某些血管疾病中起重要作用.     

血管内皮生长因子与肿瘤

血管内皮生长因子是新近确定的一种具有旁分泌机制的生长因子,能特异作用于血管内皮细胞,促进其增殖及新生血管的形成,同时还有增加血管通透性的作用．由于其生物学活性与实体瘤的生长密切相关,因此对它的研究倍受关注,进展非常迅速．     

Vascular endothelial growth factor and nitric oxide in rat liver regeneration

In this work we investigated the role of nitric oxide (NO) in the angiogenesis mediated by vascular endothelial growth factor (VEGF) during rat liver regeneration after two-thirds partial hepatectomy. Sham operated (Sh) and partially hepatectomized (PH) male Wistar rats were randomized in three experimental groups: control (treated with vehicle); pre-treated with sodium nitroprusside (SNP: 0.25 mg/kg body weight, i.v. at a rate of 1 ml/h) and pre-treated with the preferential iNOS inhibitor, aminoguanidine (AG, 100 mg/kg body weight, i.p.). Animals were killed at 5, 24 and 72 h after surgery. At 5 h post-surgery, NO production was estimated by EPR (Sh-Control: 37.65+/-10.70; PH-Control: 88.13+/-1.60(); Sh-SNP: 90.35+/-3.11(); PH-SNP: 119.5+/-12.10()(#); Sh-AG: 33.27+/-5.23, PH-AG: 36.80+/-3.40(#)) (p<0.05 vs Sh-Control; (#)p<0.05 vs PH-Control). At 24 h after PH, VEGF levels showed no difference between PH-Control and PH-SNP animals. However, after 72 h, VEGF protein levels in PH-SNP animals were found to be increased (above 300%) with respect to PH-Control. On the other hand, aminoguanidine (AG) pre-treatment blocked the rise of inhibition of NO generation and decreased VEGF expression. Our results demonstrated that NO plays a role in modulating VEGF protein expression after hepatectomy in rats.     

Vascular endothelial growth factor attenuates leukocyte-endothelium interaction during acute endothelial dysfunction: essential role of endothelium-derived nitric oxide.

Vascular endothelial growth factor (VEGF) is an endothelium-specific secreted protein that induces vasodilation and increases endothelial release of nitric oxide (NO). NO is also reported to modulate leukocyte-endothelium interaction. Therefore, we hypothesized that VEGF might inhibit leukocyte-endothelium interaction via increased release of NO from the vascular endothelium. We used intravital microscopy of the rat mesenteric microcirculation to measure leukocyte-endothelium interactions 2, 4, and 24 h after systemic administration of VEGF to the rat (120 microg/kg, i.v., bolus). Superfusion of the rat mesentery with either 0.5 U/ml thrombin or 50 microM L-NAME consistently increased the number of rolling, adhering, and transmigrated leukocytes (P<0.01 vs. control mesenteries superfused with Krebs-Henseleit buffer). At 4 and 24 h posttreatment, VEGF significantly attenuated thrombin-induced and L-NAME-induced leukocyte rolling, adherence, and transmigration in rat mesenteric venules. In addition, adherence of isolated rat PMNs to thrombin-stimulated mesenteric artery segments in vitro was significantly reduced in mesenteric arteries isolated from VEGF-treated rats (P<0.001 vs. control rats). Direct measurement of NO demonstrated a threefold increase in basal NO release from aortic tissue of rats injected with VEGF, at 4 and 24 h posttreatment (P<0. 01 vs. aortic tissue from control rats). Finally, systemic administration of VEGF to ecNOS-deficient mice failed to inhibit leukocyte-endothelium interactions observed in peri-intestinal venules. We concluded that VEGF is a potent inhibitor of leukocyte-endothelium interaction, and this effect is specifically correlated to augmentation of NO release from the vascular endothelium.--Scalia, R., Booth, G., Lefer, D. J. Vascular endothelial growth factor attenuates leukocyte-endothelium interaction during acute endothelial dysfunction: essential role of endothelium-derived nitric oxide.     

Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src.

Vascular endothelial growth factor (VEGF) is a potent endothelial cell-specific mitogen that promotes angiogenesis, vascular hyperpermeability, and vasodilation by autocrine mechanisms involving nitric oxide (NO) and prostacyclin (PGI(2)) production. These experiments used immunoprecipitation and immunoassay procedures to characterize the signaling pathways by which VEGF induces NO and PGI(2) formation in cultured endothelial cells. The data showed that VEGF stimulates complex formation of the flk-1/kinase-insert domain-containing receptor (KDR) VEGF receptor with c-Src and that Src activation is required for VEGF induction of phospholipase C gamma1 activation and inositol 1,4,5-trisphosphate formation. Reporter cell assays showed that VEGF promotes a approximately 50-fold increase in NO formation, which peaks at 5-20 min. This effect is mediated by a signaling cascade initiated by flk-1/KDR activation of c-Src, leading to phospholipase C gamma1 activation, inositol 1,4,5-trisphosphate formation, release of [Ca(2+)](i) and nitric oxide synthase activation. Immunoassays of VEGF-induced 6-keto prostaglandin F(1alpha) formation as an indicator of PGI(2) production revealed a 3-4-fold increase that peaked at 45-60 min. The PGI(2) signaling pathway follows the NO pathway through release of [Ca(2+)](i), but diverges prior to NOS activation and also requires activation of mitogen-activated protein kinase. These results suggest that NO and PGI(2) function in parallel in mediating the effects of VEGF.     

Vascular endothelial growth factor acts through novel, pregnancy-enhanced receptor signalling pathways to stimulate endothelial nitric oxide synthase activity in uterine artery endothelial cells

During pregnancy, VEGF (vascular endothelial growth factor) regulates in part endothelial angiogenesis and vasodilation. In the present study we examine the relative roles of VEGFRs (VEGF receptors) and associated signalling pathways mediating the effects of VEGF(165) on eNOS (endothelial nitric oxide synthase) activation. Despite equal expression levels of VEGFR-1 and VEGFR-2 in UAECs (uterine artery endothelial cells) from NP (non-pregnant) and P (pregnant) sheep, VEGF(165) activates eNOS at a greater level in P- compared with NP-UAEC, independently of Akt activation. The selective VEGFR-1 agonist PlGF (placental growth factor)-1 elicits only a modest activation of eNOS in P-UAECs compared with VEGF(165), whereas the VEGFR-2 kinase inhibitor blocks VEGF(165)-stimulated eNOS activation, suggesting VEGF(165) predominantly activates eNOS via VEGFR-2. Although VEGF(165) also activates ERK (extracellular-signal-regulated kinase)-1/2, this is not necessary for eNOS activation since U0126 blocks ERK-1/2 phosphorylation, but not eNOS activation, and the VEGFR-2 kinase inhibitor inhibits eNOS activation, but not ERK-1/2 phosphorylation. Furthermore, the inability of PlGF to activate ERK-1/2 and the ability of the VEGFR-2 selective agonist VEGF-E to activate ERK-1/2 and eNOS suggests again that both eNOS and ERK-1/2 activation occur predominantly via VEGFR-2. The lack of VEGF(165)-stimulated Akt phosphorylation is consistent with a lack of robust phosphorylation of Ser(1179)-eNOS. Although VEGF(165)-stimulated eNOS phosphorylation is observed at Ser(617) and Ser(635), pregnancy does not significantly alter this response. Our finding that VEGF(165) activation of eNOS is completely inhibited by wortmannin but not LY294002 implies a downstream kinase, possibly a wortmannin-selective PI3K (phosphoinositide 3-kinase), is acting between the VEGFR-2 and eNOS independently of Akt.     

Vascular endothelial growth factor is expressed in endothelial cells isolated from skeletal muscles of nitric oxide synthase knockout mice during prazosin-induced angiogenesis

In skeletal muscles, angiogenesis can be induced by increases in wall shear stress. To identify molecules involved in the angiogenic process, a method based on the use of BS-1 lectin-coated magnetic beads was developed to isolate a cellular fraction enriched in microvascular endothelial cells which are directly exposed to wall shear stress. Using such cellular fractions from skeletal muscles of C57 mice in which angiogenesis was induced by administration with the alpha(1)-adrenergic antagonist prazosin, we found the concentration of vascular endothelial growth factor (VEGF) increased in correlation to the duration of the prazosin stimulus. In contrast, the angiopoietin-2/tie-2 system was not changed even after 4days of prazosin treatment. In neuronal nitric oxide synthase (nNOS) knockout mice, the VEGF concentration was also elevated after prazosin treatment but remained almost unchanged in endothelial nitric oxide synthase (eNOS) knockout mice. However, eNOS (and not nNOS) knockout mice expressed higher levels of VEGF under non-stimulated conditions as compared to C57 mice. These results suggest that VEGF produced in endothelial cells is involved in angiogenesis in skeletal muscles of mice responding to the administration of systemic vasodilators. NO derived from eNOS and nNOS may be an important regulator of the angiogenic response in skeletal muscles in vivo.     

Vascular endothelial growth factor and its receptors

Vascular endothelial growth factor (VEGF) is a prime regulator of endothelial cell proliferation, angiogenesis, vasculogenesis and vascular permeability. Its activity is mediated by the high affinity tyrosine kinase receptors, KDR/Flk-1 and Flt-1. In this article, recently discovered structural, molecular and biological properties of VEGF are described. Among the topics discussed are VEGF and VEGF receptor structure and bioactivity, the regulation of VEGF expression, the role of VEGF and its receptors in vascular development, and the involvement of VEGF and its receptors in normal and pathological (ocular and tumor) angiogenesis.     

Effects of nitric oxide donors on vascular endothelial growth factor gene induction

Nitric oxide (NO) has been reported to modulate the vascular endothelial growth factor (VEGF) gene by accumulating hypoxia-inducible factor-1alpha (HIF-1alpha) protein, but there is a contradiction among effects of various NO donors. The effects of NO donors including S-nitroso-N-acetyl-penicillamine (SNAP), S-nitroso-glutathione (GSNO), 1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene (NOC18), 3-[(+/-)-(E)-ethyl-2(')-[(E)-hydroxyimino]-5-nitro-3-hexenecarbamoyl]-pyridine (NOR4), 3-morpholinosydnonimine (SIN-1), and nitroprusside (SNP) on the VEGF reporter gene were examined. SNAP, GSNO, NOC18, and NOR4 enhanced the VEGF reporter activity under normoxia and modulated the hypoxic induction. In contrast, SNP had only an inhibitory effect. An NO scavenger attenuated the reporter activation by NO donors except NOR4, but did not ameliorate the inhibitory effect of SNP. A reducing compound dithiothreitol suppressed NO-induced activation of the VEGF reporter gene. SNAP, GSNO, and NOC18 induced the accumulation of HIF-1alpha protein, while others did not. These results suggest that SNAP, GSNO, and NOC compounds are suitable for pharmacological studies in HIF-1-mediated VEGF gene activation by NO.     

Vascular endothelial growth factor in the lung

Vascular endothelial growth factor (VEGF) is a pluripotent growth and permeability factor that has a broad impact on endothelial cell function. The lung tissue is very rich in this protein; many different lung cells produce VEGF and also respond to VEGF. VEGF is critical for the development of the lung and serves as a maintenance factor during adult life. In addition to the physiological functions of this protein, there is increasing evidence that VEGF also plays a role in several acute and chronic lung diseases, such as acute lung injury, severe pulmonary hypertension, and emphysema. Here we provide a comprehensive overview of the rapidly expanding literature.