血管内皮生长因子的生物学及其在临床的初步应用

血管内皮生长因子(VEGF)是内皮细胞特异性的有丝分裂原。它诱导内皮细胞增殖、促进内皮细胞迁移，并抑制内皮细胞凋亡，在调节血管和淋巴管新生中起重要作用。VEGF也是胚胎发育、软骨内骨形成、女性生殖系统、以及肿瘤和眼球内血管新生所必需的。另外，VEGF也可诱导血小板粘附于血管内皮细胞而出现高凝状态。目前，有许多临床实验正在评价VEGF在血管新生依赖性疾病的促血管新生作用和抗血管新生药物用于治疗的效果。     

Ang-1/Tie2系统与病理性血管形成的关系

血管生成素1(Ang-1)是继血管内皮生长因子(VEGF)之后,人们发现的又一重要的促血管生成因子。血管生成素家族包括Ang-l、Ang-2、Ang-3、Ang-4四种分子。其共同的特异性受体为Tie-2。目前对Ang-1/Tie2系统参与新生血管形成、促进血管成熟、抑制血管渗漏及炎症的作用研究相对深入,在创伤后修复、缺血后再通、肿瘤、糖尿病并发症及子宫内膜异位等多种病理性血管形成过程中起重要作用。     

血管新生在肿瘤侵袭和器官纤维化中作用的最新认识

微血管密度与肿瘤侵袭力以及器官纤维化程度密不可分,血管新生是这两类疾病的共同靶点。然而,传统抗血管新生疗法由于肿瘤耐药性等原因而疗效有限,而以促血管新生的目标的抗纤维化疗法也因为伴随炎性反应、血管通透性改变等原因陷入瓶颈。本文探讨肿瘤和器官纤维化的在血管新生方面的内在关联。     

血管新生与疾病

很多疾病均伴有血管的变化。血管 ,特别是微血管 ,常与组织、器官的生长、发育和功能密切相关。疾病时它们发生相应的改变。有些疾病的发生发展和治疗与微血管新生有密切的联系 ,治疗时要抑制血管新生 ,如肿瘤等 ;有些疾病的发生发展有微血管的闭塞和退化 ,治疗时要促进微血管新生 ,如血栓性疾病等。因此近年来血管新生与疾病的关系在整体、细胞和分子水平上开展了广泛的研究 ,下面作一简要介绍。１肿瘤的血管新生与抗血管新生治疗１．１肿瘤血管新生肿瘤是人体细胞异常分化增殖的恶性疾病。肿瘤在表现其生长、转移等生物学行为时与其中的微…     

内皮细胞抑素与子宫内膜异位症

子宫内膜异位症(EM s)被认为是一种血管相关性疾病,大量研究证实血管内皮生长因子(VEGF)具有强大的促血管内皮增殖、促血管生成作用,与EM s的发病密切相关;另有研究表明内皮细胞抑素(endostatin)可诱导血管内皮细胞凋亡,抑制其生长和迁移,从而拮抗VEGF的促血管生成作用。本文就VEGF、endostatin对EM s发病的影响做一综述。     

血管内皮生长因子与肺疾病

血管内皮生长因子(VEGF)是一种特异地作用于血管内皮细胞的生长因子,具有促进血管内皮细胞增殖、刺激体内新生血管生成、促进血管通透性增加及维持血管正常状态和完整性的功能,它在肺癌的发生发展、低氧性肺动脉高压及肺纤维化的形成等多种肺疾病中起重要作用.     

rhbFGF基因及其蛋白促兔缺血心肌血管新生的对比研究

目的 探讨通过心肌内注射重组人碱性成纤维细胞生长因子(rhbFGF)基因及其蛋白促兔缺血心肌血管新生的“基因血管搭桥”的效果。方法 无菌条件下开胸结扎兔冠状动脉左前降支(LAD)，建立急性心肌梗死动物模型。将成功构建的真核表达质粒pcDNA3-bFGF、rhbFGF蛋白、生理盐水，直接四点注射人兔缺血心肌内。实验兔饲养6周、12周以后，通过病理切片光镜观察、图像分析对比研究三组间血管新生情况。结果 1)成功构建pcDNA3-bFGF真核表达质粒并制备rhbFGF蛋白；(2)pcDNA3-bFCF真核表达质粒在心肌中成功表达为rhbFGF蛋白；(3)血管新生的观察：通过对心肌内注射基因及其蛋白进行对比研究，发现心肌内注射蛋白和基因均有促兔缺血心肌血管新生的作用，而基因的促血管新生作用更强。结论 rhbFGF蛋白及基因心肌内注射均有促兔缺血心肌血管新生的作用，而基因的促血管新生效果显著。“基因治疗促血管新生”法是另一种有效的冠心病治疗方法，rhbFGF基因有重要的推广应用价值。     

血管内皮生长因子的研究和应用进展

血管内皮生长因子是一种多功能的细胞因子 ,参与机体多种生理、病理过程。近年来 ,大量动物实验和临床研究均表明 ,它可通过促进新生血管形成 ,加速侧枝循环建立而改善心肌血供 ,称为“治疗性血管生成”或“分子搭桥术” ,为治疗心肌缺血提供了新思路。     

糖尿病患者视网膜病变与血管内皮生长因子的关系

糖尿病视网膜病变是糖尿病患者重要的慢性并发症之一。血管内皮生长因子 (ｖａｓｃｕｌａｒｅｎｄｏｔｈｅｌｉａｌｇｒｏｗｔｈｆａｃｔｏｒ,ＶＥＧＦ)是目前所知最强的促血管生成因子 ,参与多种生理病理性新生血管形成过程。本文通过测定糖尿病视网膜病变不同周期患者血清中ＶＥＧＦ水平 ,观察ＶＥＧＦ与糖尿病视网膜病变的相关性。对象和方法1　对象　对照组 3 0例 ,为健康查体无糖尿病史与眼底疾病者 ,年龄 ( 5 7 3± 15 6)岁 ;糖尿病患者根据视网膜病变分为 3组 :①无视网膜病变 3 3例 ,男 16例 ,女 17例 ,平均年龄 ( 5 0 3±17 5 )…     

胰岛素受体与VEGF

胰岛素受体与胰岛素结合后发生自身磷酸化并磷酸化底物,启动受体后信号传导途径,在胰岛素促代谢、促细胞生长繁殖作用中起重要作用。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种病理生理过程,受缺氧、多种生长因子、高胰岛素水平等多种因素的调控。胰岛素受体及其底物作为VEGF的调控因素之一可通过多种途径影响VEGF的表达。     

Vascular Endothelial Growth Factor (VEGF) in Autoimmune Diseases

Vascular endothelial growth factor (VEGF) is a potent stimulating factor for angiogenesis and vascular permeability. There are eight isoforms with different and sometimes overlapping functions. The mechanisms of action are under investigation with emerging insights into overlapping pathways and cross-talk between other receptors such as the neuropilins, which were not previously associated to angiogenesis. VEGF has important physiological actions on embryonic development, healing, and menstrual cycle. It also has a great role in pathological conditions that are associated to autoimmune diseases. There is considerable evidence in various autoimmune diseases such as in systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis of an interrelationship between the VEGF system and theses disorders. Serum levels of VEGF correlate with disease activity in a large number of autoimmune diseases and fall with the use of standard therapy. We raised the possible future therapeutic strategies in autoimmune diseases with the anti-VEGF or anti-VEGFR (receptor). So far, this therapy has been used in cancer and macular ocular degeneration in diabetes. This review outlines the evidence for VEGF participation in various autoimmune diseases and proposes lines for future research in this field.     

Vascular Changes in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most vascular solid tumors, in which angiogenesis plays an important role. The status of angiogenesis in HCC correlates with the disease progression and prognosis, and thus provides a potential therapeutic target. This review summarizes the vascular changes and molecular and cellular basis of angiogenesis in HCC. Development of HCC is characterized by arterialization of its blood supply and sinusoidal capillarization. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that plays a critical role in mediating angiogenesis in HCC. The VEGF can function on various types of cells, such as endothelial cells, hepatic stellate cells, endothelial progenitor cells and hemangiocytes, to induce vascular changes in HCC. Therefore, blockade of VEGF‐mediated pathways, either by anti‐VEGF neutralizing antibody or tyrosine kinase inhibitors that target VEGF receptors, suppresses carcinogenesis and angiogenesis in HCC. In addition to VEGF, several other angiogenic factors in HCC have recently been identified. These factors can also regulate angiogenic processes through interaction with VEGF or VEGF‐independent pathways. Despite the fact that treatment of HCC remains a tough task due to lack of effective systemic therapy, antiangiogenic therapy has already entered clinical trials in HCC patients and sheds light on a promising novel treatment for this disease. Anat Rec, 291:721–734, 2008. © 2008 Wiley‐Liss, Inc.     

Triptolide Suppresses Alkali Burn‐Induced Corneal Angiogenesis Along with a Downregulation of VEGFA and VEGFC Expression

Triptolide (TPL) is an active compound extracted from a Chinese herbal medicine tripterygium wilfordii Hook. f. (Celastraceae), which has been used as an anti‐inflammatory drug for years. It also inhibits the growth and proliferation of different types of cancer cells. The inhibitory effect of TPL on angiogenesis after chemical‐induced corneal inflammation was studied in vivo. The effects of TPL on the proliferation, apoptosis, migration, and tube formation of rat aortic endothelial cells (RAECs) were studied in vitro. Cell proliferation and apoptosis were measured by MTT assay and flow cytometry, respectively. Migration was analyzed using the scratch wound healing assay and transwell assay. Tube formation assay was used to examine angiogenesis. Real‐time PCR and Western blot were used to determine the expression of vascular endothelial growth factor A (VEGFA) and VEGFC. To study the in vivo effects of TPL, the mouse model of alkali burn‐induced corneal angiogenesis was used. The angiogenesis was analyzed by determining the density of the newly generated blood vessels in corneas. We found that TPL induced apoptosis and inhibited the proliferation of RAECs in a dose‐dependent manner. TPL inhibited migration and tube formation of RAECs and decreased the expression of VEGFA and VEGFC in vitro. Furthermore, TPL suppressed alkali burn‐induced corneal angiogenesis and inhibited the expression of VEGFA and VEGFC in corneas in vivo. In conclusion, topical TPL as a pharmacological agent has the ability to reduce angiogenesis in cornea and may have clinical indications for the treatment of corneal angiogenesis diseases which have to be further explored. Anat Rec, 300:1348–1355, 2017. © 2017 Wiley Periodicals, Inc.     

The evolving concept of physiological ischemia training vs. ischemia preconditioning

Ischemic heart diseases are the leading cause of death with increasing numbers of patients worldwide. Despite advances in revascularization techniques, angiogenic therapies remain highly attractive. Physiological ischemia training, which is first proposed in our laboratory, refers to reversible ischemia training of normal skeletal muscles by using a tourniquet or isometric contraction to cause physiologic ischemia for about 4 weeks for the sake of triggering molecular and cellular mechanisms to promote angiogenesis and formation of collateral vessels and protect remote ischemia areas. Physiological ischemia training therapy augments angiogenesis in the ischemic myocardium by inducing differential expression of proteins involved in energy metabolism, cell migration, protein folding, and generation. It upregulates the expressions of vascular endothelial growth factor, and induces angiogenesis, protects the myocardium when infarction occurs by increasing circulating endothelial progenitor cells and enhancing their migration, which is in accordance with physical training in heart disease rehabilitation. These findings may lead to a new approach of therapeutic angiogenesis for patients with ischemic heart diseases. On the basis of the promising results in animal studies, studies were also conducted in patients with coronary artery disease without any adverse effect in vivo, indicating that physiological ischemia training therapy is a safe, effective and non-invasive angiogenic approach for cardiovascular rehabilitation. Preconditioning is considered to be the most protective intervention against myocardial ischemia-reperfusion injury to date. Physiological ischemia training is different from preconditioning. This review summarizes the preclinical and clinical data of physiological ischemia training and its difference from preconditioning.     

血管内皮生长因子与甲状腺疾病研究进展

血管内皮生长因子(VEGF)的基本功能是促进血管生长。近年研究表明,VEGF通过影响病灶处血管或癌细胞自身的生成从而在多种甲状腺疾病中发挥着重要作用。但VEGF的功能以及在不同甲状腺疾病中的具体变化情况仍然需要进一步探索。本文对VEGF的分子生物学及生物学特性、在多种甲状腺疾病中的作用及其临床应用进行简要综述。     

Tumor angiogenesis in the bone marrow of multiple myeloma patients and its alteration by thalidomide treatment

Angiogenesis in solid tumors is important to tumor growth, invasion and metastasis. Recently, it has been suggested that angiogenesis plays a certain role in the development of hematopoietic malignancies, including leukemia and multiple myeloma. We evaluated tumor angiogenesis in the bone marrow (BM) of multiple myeloma (MM) patients by calculating microvessel density (MVD) in needle-biopsy specimens obtained from 51 cases of untreated MM or monoclonal gammopathy of undetermined significance (MGUS). The MVD in the BM of donors for transplantation and patients with non-hematological diseases was calculated as a control. There was an obvious increase in MVD in the BM of MM patients, and the MVD correlated with the grade of myeloma cell invasion of the BM in the untreated MM cases. It was recently reported that thalidomide might be effective for the treatment of MM. We assessed the effect of thalidomide on angiogenesis in BM treatment of 11 patients with refractory MM. The concentration of M-protein in the serum or urine of seven of the 11 patients was reduced by at least 30% after thalidomide treatment, and MVD in the BM decreased in three of these seven cases in response to thalidomide. Increased plasma concentrations of basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF) were observed in all 11 cases before thalidomide administration and both levels were reduced after treatment with thalidomide. Augmented angiogenesis in the bone marrow of MM patients was confirmed in the present study. It seems that thalidomide is effective in the treatment of MM through the impairment of angiogenesis by decreasing FGF-2 and VEGF production. This is the first report on pathological evidence in the bone marrow of MM before and after thalidomide treatment, in Japan.     

Determinants of placental vascularity

PROBLEM: Vascular growth during implantation and placentation is critical for successful gestation and it is thought that vascular insufficiencies during placentation contribute to a number of obstetrical complications. However, relatively little is known regarding the regulation of angiogenesis in the placenta. METHOD OF STUDY: We review literature concerning the potential significance of inadequate placental vascularity as a contributor to the obstetrical complications of spontaneous abortion, fetal growth restriction and preeclampsia. Gene expression assays were used to compare fluctuations of placenta growth factor (PlGF) and PlGF receptor expression in normal and preeclamptic trophoblast in vitro. RESULTS: Studies have shown that common obstetrical complications manifest altered placental vascularity. Both intrinsic defects (gene knockouts) and extrinsic factors (O(2) tension, cytokines, etc) may be responsible for the defects. Some of these factors have been shown to influence trophoblast vascular endothelial growth factor (VEGF)/PlGF expression suggesting this particular family of angiogenic proteins play an important role in placental angiogenesis. CONCLUSION: Placental vascularization reflects a complex interaction of regulatory factors. Understanding the regulation of vascular growth in the placenta will provide much needed insight into placenta-related vascular insufficiencies.     

Vascular endothelial growth factor in children with cyanotic and acyanotic and congenital heart disease

Introduction

Vascular endothelial growth factor is a potent stimulator of angiogenesis. Children with cyanotic congenital heart disease often experience the development of widespread formation of collateral blood vessels, which may represent a form of abnormal angiogenesis resulting in increased morbidity and mortality. We undertook the present study to determine whether children with cyanotic congenital heart disease have elevated serum levels of vascular endothelial growth factor compared to children with acyanotic heart disease.

Material and methods

Serum was obtained from 35 children with cyanotic congenital heart disease and 30 children with acyanotic heart disease. Vascular endothelial growth factor levels were measured in the serum of these patients by sandwich enzyme immunoassay.

Results

Vascular endothelial growth factor was significantly elevated in children with cyanotic congenital heart disease compared to children with acyanotic heart disease (150.3 ±48.1 vs. 85.4 ±18.7 pg/ml, respectively, p < 0.001). In the cyanotic group, oxygen saturation (SaO₂) was negatively correlated with VEGF (r=–0.631, p < 0.001) while haemoglobin was positively correlated (r=0.781, p = 0.007). No significant correlations were found in the acyanotic group.

Conclusions

Children with cyanotic congenital heart disease have elevated systemic levels of vascular endothelial growth factor directly related to the degree of cyanosis (SaO₂ and haemoglobin levels). These findings suggest that the widespread formation of collateral vessels in these children may be mediated by vascular endothelial growth factor.     

An eosinophil immune response characterizes the inflammatory skin disease observed in Tie-2 transgenic mice

Although mouse models of inflammatory skin diseases such as psoriasis and atopic dermatitis fail to completely phenocopy disease in humans, they provide invaluable tools to examine the molecular and cellular mechanisms responsible for the epidermal hyperplasia, inflammation, and excess angiogenesis observed in human disease. We have previously characterized a tyrosine kinase with immunoglobin-like and epidermal growth factor-like domain-2 (Tie-2) transgenic mouse model of an inflammatory skin disease exhibiting these features. More specifically, we demonstrated that the inflammatory component consisted of increased infiltration of CD3-positive T lymphocytes and mast cells in the skin. Here, we further characterize the inflammatory component in the blood and skin of Tie-2 transgenic mice at cellular and molecular levels. We observed increased numbers of CD3-positive T lymphocytes in the blood and increased infiltration of eosinophils in the skin. Furthermore, we characterized cytokine protein and gene expression in the blood and skin, respectively, and observed the deregulated expression of cytokines associated with Th1 and eosinophil immune responses. Interestingly, treatment of Tie-2 transgenic mice with anti-CD4 antibody appeared to resolve aspects of inflammation but did not resolve epidermal hyperplasia, suggesting an important role for eosinophils in mediating the inflammatory skin disease observed in Tie-2 transgenic mice.