血管内皮生长因子受体的信号转导通路

血管内皮生长因子受体(VEGFR)是VEGF的特异性受体,由于在刺激血管内皮细胞增殖、迁移、管腔形成,促进肿瘤生长和转移过程中起着重要的作用,而成为抗肿瘤新生血管生成的热点。该主要围绕VEGF及其不同受体的信号转导通路作一综述。     

内皮抑素在新生血管形成相关疾病中的作用机制研究进展

新血管形成是许多生理、病理过程的关键步骤,受血管形成促进因子和抑制因子的调节。内皮抑素是最重要的血管形成抑制因子之一,可在体外抑制血管内皮细胞的增殖、迁移和血管化,在动物模型中抑制新血管形成,对新生血管形成相关疾病,特别是肿瘤有治疗作用。关于内皮抑素抑制新血管形成的分子机制尚无定论,已有线索表明,它可通过与VEGF、MMP-2、整合素以及VEGF受体KDR等相互作用,从而抑制内皮细胞增殖、迁移或通过多种途径促进内皮细胞凋亡。本就内皮抑素作用的分子机制,及其作用于新血管形成相关疾病的最新研究成果进行综述。     

血管内皮生长因子在乳腺癌淋巴道转移中作用的研究进展

血管内皮生长因子(VSGF)是一种重要的血管生成刺激因子,是特异作用于血管内皮细胞、上调血管生成的重要因子,能刺激血管内皮细胞增殖、迁移和诱导血管生成,其家族中VEGF-C、VEGF-D和VEGFR-3在乳腺癌淋巴道转移中起重要作用,可以作为乳腺癌患者的独立预后判断因素.以VEGF为靶点的抗血管化治疗成为治疗乳腺癌的新方法,通过对VEGF信号通路的抑制是目前抗癌治疗研究热点之一.     

血管内皮生长因子受体-2所介导信号通路的研究进展

血管新生是许多生理和病理进程发生的重要机理．在生物体内,血管新生需经过多步精细调控历程,现有研究表明,血管内皮生长因子(VEGF)及其受体蛋白酪氨酸激酶,尤其是血管内皮生长因子受体-2(VEGFR-2)所介导的信号级联通路是其中关键性的调节途径．VEGF/VEGFR-2所介导的信号级联通路可以调控血管内皮细胞的增殖、迁移、存活和通透性的改变,促进血管的新生．VEGF与VEGFR-2的胞外区特异性结合后,引起受体的二聚化和自身的交互磷酸化,使胞内特定的酪氨酸残基磷酸化．下游信号蛋白可以通过其Src同源结构域-2(SH2)与VEGFR-2结合,随后激活下游的效应蛋白,调控内皮细胞的生物学活性．此外,VEGF/VEGFR-2信号通路还可以下调树突细胞(DC)的活性．对VEGF/VEGFR-2信号通路作用的深入了解,将有助于新药的研发．     

VEGF受体信号转导在冠心病治疗中的研究现状

血管内皮细胞生长因子(VEGF)受体信号转导途径参与细胞的迁移、增殖、生存,在血管新生和血管保护中具有重要的作用.VEGF受体信号转导途径可能是治疗冠状动脉粥样硬化的理想靶点.本文针对VEGF受体信号转导途径及其与冠心病治疗的研究现状予以综述.     

内皮细胞增殖抑制因子研究进展

内皮细胞过度增殖引起的病理性血管生成是肿瘤、类风湿性关节炎等发病的关键环节。内皮细胞增殖由血管内皮细胞生长因子等促血管生成因子提供促增殖信号,而新近发现的多种内皮增殖抑制因子,如血管内皮抑素、血管抑素、血小板反应蛋白-1、微囊蛋白1、某些microRNAs和某些抑癌基因等,则通过抑制促增殖信号、调节细胞周期、诱导细胞凋亡等途径下调内皮细胞的增殖及血管生成。内皮增殖抑制因子可望成为病理性血管生成防治的新靶点。     

血管内皮生长因子受体信号转导通路与肿瘤血管生成

血管内皮生长因子是促进血管生成的重要调节因子.它能促进内皮细胞增殖、迁移,阻止内皮细胞凋亡、管腔网状结构退化,增加血管渗透性.所有这些作用都是通过血管内皮生长因子受体信号转导通路实现的.它们在肿瘤血管生成、肿瘤生长中起着重要的作用.以血管内皮生长因子受体信号转导通路为靶点是开发肿瘤血管生成抑制剂的理想策略.     

阻断VEGF旁分泌通路抑制乳腺癌血管生成与肿瘤生长

以人乳腺癌细胞株MCF 7为研究对象 ,通过构建有义与反义血管内皮生长因子 (VEGF)基因表达质粒 ,并转染MCF 7细胞 ,建立了高与低水平表达VEGF的细胞克隆。稳定转染反义VEGF表达质粒的细胞产生和分泌VEGF的能力明显下降 ,尽管在体外培养条件下细胞的增殖速度与未经转染的对照相比不是减慢而是略有增快 ,但在体内的成瘤能力、生长速度和转移能力等却明显低于未经转染的对照细胞或稳定转染有义VEGF表达质粒高水平表达VEGF的细胞克隆。通过体内电穿孔技术介导反义VEGF12 1及可溶性VEGF受体sFlk 1表达质粒转移至荷瘤鼠肿瘤组织内 ,反义VEGF12 1及sFlk 1的表达能显著抑制肿瘤的生长。研究结果证实了VEGF旁分泌通路在诱导乳腺癌肿瘤血管生成、促进肿瘤生长和转移方面起重要作用 ,阻断VEGF旁分泌通路能有效抑制乳腺癌的生长     

Delta样配体4与血管生成

Notch信号转导途径参与了许多重要的发育过程,如神经发育、血管形成等,最近的一系列研究表明Notch受体与邻近细胞配体--Delta样配体4（Dll-4）共同参与了新生血管的生长和分支,通过抑制血管内皮顶端细胞的形成,细胞密度、位置以及行为方式的调节,而有效促进血管内皮细胞的正常分化和血管网的及时形成.Dll4在血管生成过程中的作用为相关疾病发生机制的理解、临床诊断及治疗提供了重要的帮助.     

VEGF和Notch通路在肝癌血管形成中的作用

血管内皮生长因子(vascular endothelial growth factor,VEGF)和Notch信号通路在血管新生及肿瘤血管生成过程发挥极重要的作用。VEGF被认为是血管生成的刺激因子,可启动血管生成,而Notch信号通路则在肿瘤血管生成过程发挥负反馈作用,防止血管过度生成,两者的协调作用保证形成的血管具有一定功能,确保肿瘤生长的氧供。同时阻断DLL4/Notch和VEGF具有协同作用,既能降低肿瘤血管的密度及功能,又抑制肿瘤生长。如果能证实VEGF/Notch信号网络在肝癌新生血管中的作用,可以为肝癌的治疗提供新的思路。     

Autocrine functions of VEGF in breast tumor cells

Vascular endothelial growth factor A (VEGF-A) is well known for its key roles in blood vessel growth. Although most studies on VEGF and VEGF receptors have been focused on their functions in angiogenesis and in endothelial cells, the role of VEGF in cancer biology appears as an emerging area of importance. In this context, the presence of VEGF receptors in tumor cells strongly suggests that VEGF-A also promotes a wide range of functions, both in vitro and in vivo, all autocrine functions on tumor cells, including adhesion, survival, migration and invasion. Ultimately, refining our knowledge of VEGF signaling pathways in tumor cells should help us to understand why the current used treatments targeting the VEGF pathway in cancer are not universally effective in inhibiting metastasis tumors, and it should also provide new avenues for future therapies.     

Autocrine functions of VEGF in breast tumor cells: Adhesion,survival, migration and invasion

Vascular endothelial growth factor A (VEGF-A) is well known for its key roles in blood vessel growth. Although most studies on VEGF and VEGF receptors have been focused on their functions in angiogenesis and in endothelial cells, the role of VEGF in cancer biology appears as an emerging area of importance. In this context, the presence of VEGF receptors in tumor cells strongly suggests that VEGF-A also promotes a wide range of functions, both in vitro and in vivo, all autocrine functions on tumor cells, including adhesion, survival, migration and invasion. Ultimately, refining our knowledge of VEGF signaling pathways in tumor cells should help us to understand why the current used treatments targeting the VEGF pathway in cancer are not universally effective in inhibiting metastasis tumors, and it should also provide new avenues for future therapies.     

Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF)

Vascular endothelial growth factor (VEGF) was originally identified as an endothelial cell specific growth factor stimulating angiogenesis and vascular permeability. Some family members, VEGF C and D, are specifically involved in lymphangiogenesis. It now appears that VEGF also has autocrine functions acting as a survival factor for tumour cells protecting them from stresses such as hypoxia, chemotherapy and radiotherapy. The mechanisms of action of VEGF are still being investigated with emerging insights into overlapping pathways and cross-talk between other receptors such as the neuropilins which were not previously associated with angiogenesis. VEGF plays an important role in embryonic development and angiogenesis during wound healing and menstrual cycle in the healthy adult. VEGF is also important in a number of both malignant and non-malignant pathologies. As it plays a limited role in normal human physiology, VEGF is an attractive therapeutic target in diseases where VEGF plays a key role. It was originally thought that in pathological conditions such as cancer, VEGF functioned solely as an angiogenic factor, stimulating new vessel formation and increasing vascular permeability. It has since emerged it plays a multifunctional role where it can also have autocrine pro-survival effects and contribute to tumour cell chemoresistance. In this review we discuss the established role of VEGF in angiogenesis and the underlying mechanisms. We discuss its role as a survival factor and mechanisms whereby angiogenesis inhibition improves efficacy of chemotherapy regimes. Finally, we discuss the therapeutic implications of targeting angiogenesis and VEGF receptors, particularly in cancer therapy.     

Human EP3(I) prostanoid receptor induces VEGF and VEGF receptor-1 mRNA expression

A critical event in tumor development is the formation of new blood vessels to provide oxygen, nutrients and growth factors to the rapidly growing cancer cells. This process of angiogenesis is complex, however, it is well established that vascular endothelial growth factor (VEGF)-mediated signaling is an important early event. Knockout mice studies have implicated the EP3 receptor in tumor development and angiogenesis; however, the signaling mechanism involved with this effect is unclear. We now show that stimulation of the EP3_I isoform of the human EP3 receptor with prostaglandin E₂ increases the mRNA expression of both VEGF and its cognate receptor VEGF receptor-1 (VEGFR-1). These inductions by the EP3_I receptor involve the sequential activation of phosphatidylinositol 3-kinase and the extracellular signal-regulated kinases. Up-regulation of VEGF and VEGFR-1 mRNA by the human EP3_I receptor has not been previously reported and further strengthen the role of this receptor in tumor-associated angiogenesis.     

Proteomic studies of rat tibialis anterior muscle during postnatal growth and development

Phosphoinositide 3-kinase (PI3K) pathway exerts its effects through Akt, its downstream target molecule, and thereby regulates various cell functions including cell proliferation, cell transformation, apoptosis, tumor growth, and angiogenesis. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has been implicated in regulating cell survival signaling through the PI3K/Akt pathway. However, the mechanism by PI3K/PTEN signaling regulates angiogenesis and tumor growth in vivo remains to be elucidated. Vascular endothelial growth factor (VEGF) plays a pivotal role in tumor angiogenesis. The effect of PTEN on VEGF-mediated signal in pancreatic cancer is unknown. This study aimed to determine the effect of PTEN on both the expression of VEGF and angiogenesis. Toward that end, we used the siRNA knockdown method to specifically define the role of PTEN in the expression of VEGF and angiogenesis. We found that siRNA-mediated inhibition of PTEN gene expression in pancreatic cancer cells increase their VEGF secretion, up-modulated the proliferation, and migration of co-cultured vascular endothelial cell and enhanced tubule formation by HUVEC. In addition, PTEN modulated VEGF-mediated signaling and affected tumor angiogenesis through PI3K/Akt/VEGF/eNOS pathway.     

VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells.

Vascular endothelial growth factor (VEGF) has been shown to promote neovascularization in animal models and, more recently, in human subjects. This feature has been assumed to result exclusively from its direct effects on fully differentiated endothelial cells, i.e. angiogenesis. Given its regulatory role in both angiogenesis and vasculogenesis during fetal development, we investigated the hypothesis that VEGF may modulate endothelial progenitor cell (EPC) kinetics for postnatal neovascularization. Indeed, we observed an increase in circulating EPCs following VEGF administration in vivo. VEGF-induced mobilization of bone marrow-derived EPCs resulted in increased differentiated EPCs in vitro and augmented corneal neovascularization in vivo. These findings thus establish a novel role for VEGF in postnatal neovascularization which complements its known impact on angiogenesis.     

VEGF165 induces differentiation of hair follicle stem cells into endothelial cells and plays a role in in vivo angiogenesis

Within the vascular endothelial growth factor (VEGF) family of five subtypes, VEGF165 secreted by endothelial cells has been identified to be the most active and widely distributed factor that plays a vital role in courses of angiogenesis, vascularization and mesenchymal cell differentiation. Hair follicle stem cells (HFSCs) can be harvested from the bulge region of the outer root sheath of the hair follicle and are adult stem cells that have multi‐directional differentiation potential. Although the research on differentiation of stem cells (such as fat stem cells and bone marrow mesenchymal stem cells) to the endothelial cells has been extensive, but the various mechanisms and functional forms are unclear. In particular, study on HFSCs’ directional differentiation into vascular endothelial cells using VEGF165 has not been reported. In this study, VEGF165 was used as induction factor to induce the differentiation from HFSCs into vascular endothelial cells, and the results showed that Notch signalling pathway might affect the differentiation efficiency of vascular endothelial cells. In addition, the in vivo transplantation experiment provided that HFSCs could promote angiogenesis, and the main function is to accelerate host‐derived neovascularization. Therefore, HFSCs could be considered as an ideal cell source for vascular tissue engineering and cell transplantation in the treatment of ischaemic diseases.     

Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis

The VEGF/VPF (vascular endothelial growth factor/vascular permeability factor) ligands and receptors are crucial regulators of vasculogenesis, angiogenesis, lymphangiogenesis and vascular permeability in vertebrates. VEGF-A, the prototype VEGF ligand, binds and activates two tyrosine kinase receptors: VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). VEGFR1, which occurs in transmembrane and soluble forms, negatively regulates vasculogenesis and angiogenesis during early embryogenesis, but it also acts as a positive regulator of angiogenesis and inflammatory responses, playing a role in several human diseases such as rheumatoid arthritis and cancer. The soluble VEGFR1 is overexpressed in placenta in preeclampsia patients. VEGFR2 has critical functions in physiological and pathological angiogenesis through distinct signal transduction pathways regulating proliferation and migration of endothelial cells. VEGFR3, a receptor for the lymphatic growth factors VEGF-C and VEGF-D, but not for VEGF-A, regulates vascular and lymphatic endothelial cell function during embryogenesis. Loss-of-function variants of VEGFR3 have been identified in lymphedema. Formation of tumor lymphatics may be stimulated by tumor-produced VEGF-C, allowing increased spread of tumor metastases through the lymphatics. Mapping the signaling system of these important receptors may provide the knowledge necessary to suppress specific signaling pathways in major human diseases.     

EVL regulates VEGF receptor‐2 internalization and signaling in developmental angiogenesis

Endothelial tip cells are essential for VEGF‐induced angiogenesis, but underlying mechanisms are elusive. The Ena/VASP protein family, consisting of EVL, VASP, and Mena, plays a pivotal role in axon guidance. Given that axonal growth cones and endothelial tip cells share many common features, from the morphological to the molecular level, we investigated the role of Ena/VASP proteins in angiogenesis. EVL and VASP, but not Mena, are expressed in endothelial cells of the postnatal mouse retina. Global deletion of EVL (but not VASP) compromises the radial sprouting of the vascular plexus in mice. Similarly, endothelial‐specific EVL deletion compromises the radial sprouting of the vascular plexus and reduces the endothelial tip cell density and filopodia formation. Gene sets involved in blood vessel development and angiogenesis are down‐regulated in EVL‐deficient P5‐retinal endothelial cells. Consistently, EVL deletion impairs VEGF‐induced endothelial cell proliferation and sprouting, and reduces the internalization and phosphorylation of VEGF receptor 2 and its downstream signaling via the MAPK/ERK pathway. Together, we show that endothelial EVL regulates sprouting angiogenesis via VEGF receptor‐2 internalization and signaling.     

Effects of inflammatory factors on mesenchymal stem cells and their role in the promotion of tumor angiogenesis in colon cancer

Mesenchymal stem cells (MSCs), which are modulated by cytokines present in the tumor microenvironment, play an important role in tumor progression. It is well documented that inflammation is an important part of the tumor microenvironment, so we investigated whether stimulation of MSCs by inflammatory cytokines would contribute to their ability to promote tumor growth. We first showed that MSCs could increase C26 colon cancer growth in mice. This growth-promoting effect was further accelerated when the MSCs were pre-stimulated by inflammatory factors IFN-γ and TNF-α. At the same time, we demonstrated that MSCs pre-stimulated by both inflammatory factors could promote tumor angiogenesis in vivo to a greater degree than untreated MSCs or MSCs pre-stimulated by either IFN-γ or TNF-α alone. A hen egg test-chorioallantoic membrane (HET-CAM) assay showed that treatment of MSC-conditioned medium can promote chorioallantoic membrane angiogenesis in vitro, especially treatment with conditioned medium of MSCs pretreated with IFN-γ and TNF-α together. This mechanism of promoting angiogenesis appears to take place via an increase in the expression of vascular endothelial growth factor (VEGF), which itself takes place through an increase in signaling in the hypoxia-inducible factor 1α (HIF-1α)-dependent pathway. Inhibition of HIF-1α in MSCs by siRNA was found to effectively reduce the ability of MSC to affect the growth of colon cancer in vivo in the inflammatory microenviroment. These results indicate that MSCs stimulated by inflammatory cytokines such as IFN-γ and TNF-α in the tumor microenvironment express higher levels of VEGF via the HIF-1α signaling pathway and that these MSCs then enhance tumor angiogenesis, finally leading to colon cancer growth in mice.