血管平滑肌细胞增殖、迁移的相关信号转导机制

血管平滑肌细胞(VSMC)向内膜增殖和迁移是动脉粥样硬化斑快形成、高血压、血管再狭窄等疾病的共同发病基础之一,多种信号转导通路参与了VSMC增殖、迁移,因此研究相关信号转导机制对上述疾病的防治有重要意义。     

凝血酶促血管平滑肌细胞增殖的信号转导研究进展

血管平滑肌细胞异常增殖在动脉粥样硬化和血管成形术后狭窄等血管增殖性疾病的发病机制中起着重要作用.近来研究表明,凝血酶具有生长激素样作用,参与了血管增殖性疾病的发展.本文就凝血酶及其受体的特性,促血管平滑肌细胞(VSMC)增殖的信号转导作一综述.     

凝血酶促血管平滑肌细胞增殖的信号转导研究进展

血管平滑肌细胞异常增殖在动脉粥样硬化和血管成形术后狭窄等血管增殖性疾病的发病机制中起着重要作用。近年来研究表明，凝血酶具有生长激素样作用，参与了血管增殖性疾病的发展，本文就凝血酶及其受体的特性，促血管平滑肌细胞（VSMC）增殖的信号转号作一综述。     

信号转导子和激活子3通路调控大鼠血管平滑肌细胞增殖迁移机制研究

目的研究转录信号转导子和激活子3（stat3）通路与大鼠血管平滑肌细胞（VSMCs）增殖迁移的关系,明确VSMCs增殖的信号转导过程。方法应用脂质体转染Stat3反义寡核苷酸作用于大鼠VSMCs,应用酶联免疫法（ELISA）检测Stat3水平变化及MTF法检测细胞增殖状态,蛋白免疫印迹法（Western blot）检测stat3、磷酸化stat3及其靶基因产物Cyclin D1、Bcl—XL的表达。结果转染Stat3反义寡核苷酸后,大鼠VSMCs中Stat3水平明显下降（P〈0．01）,同时其增殖水平降低,而相应空白对照组、脂质体组、转染正义寡核苷酸组变化不明显。转染Stat3反义寡核苷酸的VSMCs中stat3、p-Stat 3、Cyclin D1蛋白表达水平随作用时间延长而下降（P〈0．01）,而Bcl—xL水平无明显变化。结论癌基因stat3信号通路与大鼠VSMCs增殖高度相关,可能通过其下游靶基因Cyclin D1影响其增殖,而阻断此通路则可抑制VSMCs的增殖。     

血管平滑肌细胞增殖和迁移的信号传导调控及其研究进展

动脉中膜平滑肌细胞向内膜的迁移和增殖 ,在动脉粥样硬化和经皮腔内冠状动脉成行术 (PTCA)术后再狭窄等发病机制中起着重要作用。其在增殖和迁移过程中受蛋白激酶C、Ca2 /钙调蛋白依赖性蛋白激酶Ⅱ、磷脂酰肌醇3 激酶 /蛋白激酶B、丝裂原激动蛋白激酶等多种信号传导通路调节。本文就血管平滑肌细胞 (VSMC)增殖和迁移的这些信号传导通路及其治疗的最新研究进展作一综述。     

血管平滑肌细胞增殖及其调控

血管壁受损是导致血管平滑肌细胞增殖的起始原因,损伤刺激通过细胞内的信号转导可引起许多原瘤基因的表达和细胞的因子生成,从而使血管平滑肌细胞增殖和凋亡的平衡被打破,导致血管平滑肌细胞过分增殖,通过干预细胞内信号转导通路或／和调节相关基因的表达以阻断血管平滑肌细胞增殖可望成为治疗此类心血管疾病的有效途径。     

血管平滑肌细胞表型转化及相关信号转导机制探讨

血管平滑肌细胞增殖是血管成形术后再狭窄、动脉粥样硬化斑块形成的病理基础。血管平滑肌细胞增殖能力与其表型转化密切相关。对从血管平滑肌细胞表型转化的主要特征、标志物、信号转导机制进行了探讨。     

欧亚旋覆花总黄酮对血管平滑肌细胞增殖和迁移的影响

目的 探讨欧亚旋覆花总黄酮(TFIB)对培养血管平滑肌细胞(VSMC)增殖及迁移的影响.方法 采用大鼠胸腹主动脉的动脉中膜平滑肌细胞,用贴块法培养,实验用4～7代细胞,加入不同浓度的TFIB共同孵育24 h.采用噻唑蓝(MTT)法观察该药对细胞增殖的影响,倒置显微镜下观察该药对细胞迁移的影响.结果 与对照组相比,TFIB对VSMC增殖具有抑制作用,该作用呈剂量依赖性;随着TFIB浓度增加体外培养的VSMC迁移距离缩短.结论 适宜浓度的TFIB可明显抑制体外培养的大鼠VSMC的增殖、迁移.     

血管平滑肌细胞迁移的调控机制

现今认为血管平滑肌细胞(vascular smooth muscle cells，VSMC)的增殖是动脉粥样硬化发展和气囊血管成型术后(PCI)再狭窄的一个关键因素，而增殖的平滑肌细胞由血管中层向内膜的迁移是内膜增厚的一个重要机制。VSMC迁移的结果可导致内膜中VSMC的大量积聚和结缔组织的形成，进而促进新生内膜形成和动脉粥样硬化。     

Gremlin promotes vascular smooth muscle cell proliferation and migration

Recent reports highlight the importance of BMP in the vasculature. We investigated the expression pattern and role of the BMP antagonist gremlin in VSMC. We detected gremlin mRNA constitutive expression in adult and embryonic rat aortic VSMC, and in rat carotids. In vitro analysis demonstrated that angiotensin II, TGF-β1 and PDGF induced significant changes in gremlin mRNA expression. Gremlin stable overexpression in A7r5 cells blocked BMP signaling. BMP-induced reduction in VSMC DNA synthesis was markedly inhibited by gremlin overexpression. In fact, gremlin overexpression increased DNA synthesis and cell counts, and accelerated cell cycle progression of VSMC, through mechanisms that include p27^kip1 down-regulation. Gremlin also led to marked increments in VSMC migration. In addition, gremlin gene silencing promoted a significant blockade on cell proliferation and migration. In vivo studies disclosed increased gremlin protein expression in the neointima of balloon-injured carotid arteries. In summary, the BMP antagonist gremlin is constitutively expressed in the normal vasculature. Gremlin induces VSMC proliferation and migration and is significantly regulated by growth factors and injury. We postulate that gremlin plays a part in the development of pathological phenotypic changes of adult VSMC.     

激肽释放酶-激肽系统在血管平滑肌细胞增殖和迁移中的作用

血管平滑肌细胞(vascular smooth muscle cell,VSMC)增殖和迁移在动脉粥样硬化以及血管内支架成形术后再狭窄的发生和发展中起着重要作用.近年来的研究显示,激肽释放酶-激肽系统(kallikrein-kinin system,KKS)在细胞因子和转导通路方面与VSMC增殖和迁移密切相关.因此,探讨KKS在VSMC增殖和迁移过程中的作用,对于临床防治动脉粥样硬化、血管内支架成形术后再狭窄具有十分重要的意义.     

Extracellular matrix glycoprotein biglycan enhances vascular smooth muscle cell proliferation and migration

Proteoglycans are produced and secreted by vascular smooth muscle cells, but the pathophysiological role of these glycoproteins in the vasculature is an enigma. Because the small leucine-rich proteoglycan (SLRP) biglycan is overexpressed in arteriosclerotic lesions, we produced mice constitutively overexpressing biglycan in the vascular smooth muscle, in order to examine the effects on vascular pathology. In the aorta and renal vasculature, increased vascular proliferation was seen both in the basal state and after infusion of angiotensin II (Ang II) in the transgenic mice compared with wild-type controls. In addition, the combination of biglycan overexpression and Ang II infusion resulted in marked increases in vascular smooth muscle cell proliferation and migration in the coronary arteries, as well as increases in fibrosis surrounding the vessels. In vitro, biglycan caused an increase in thymidine incorporation and migration of vascular smooth muscle cells, whereas these parameters were unchanged or reduced in endothelial cells. Moreover, addition of biglycan resulted in an increase in cdk2 expression and decrease in p27 levels in the vascular smooth muscle cells. These results suggest that this extracellular matrix SLRP may be involved in the regulation of vascular smooth muscle growth and migration through cdk2- and p27-dependent pathways. Furthermore, changes in biglycan expression could be a factor influencing the susceptibility of arteries to vascular injury, and may play a direct role in the pathogenesis of vascular lesions.     

大黄素自身抑制血管平滑肌细胞迁移和增殖

目的探讨大黄素对血管平滑肌细胞迁移和增殖的作用以及大黄素在血管平滑肌细胞中是否存在代谢过程。方法采用Transwell迁移系统和MTT法观察大黄素对血管平滑肌细胞迁移和增殖的影响。结果大黄素能显著抑制平滑肌细胞迁移,5μg/mL大黄素抑制率为83·3%;大黄素呈浓度和时间依赖性抑制平滑肌细胞增殖。然而,血管平滑肌细胞作用24h后,上清液中的大黄素浓度并无显著降低;细胞色素p450氧化酶诱导剂或者抑制剂没有改变大黄素的细胞毒性作用或者细胞内活性氧水平。大黄素的主要代谢酶(细胞色素p450氧化酶)基因表达水平没有显著的上调。结论大黄素能够抑制血管平滑肌细胞的迁移和增殖,并且不被平滑肌细胞代谢,可能作为药物涂层支架的药物。     

MicroRNA-29a对血管平滑肌细胞增殖和迁移的影响

目的 研究MicroRNA-29 a对血管平滑肌细胞(VSMC)增殖和迁移的影响并探讨其可能机制.方法 通过MTT法和划痕法分别观察microRNA-29a对VSMCs活力和迁移能力的影响;通过Realtime-PCR和Western印迹检测分别观察micro-RNA-29 a对MMP-9、MMP-2和PCNA表达的影响.结果 与阴性对照组和空白对照组相比较,MicroRNA-29 a反义寡核苷酸组VSMC体外增殖能力和迁移能力明显被抑制(P＜0.05);Realtime-PCR和Western印迹检测发现与阴性对照组和空白对照组相比较,MicroRNA-29 a反义寡核苷酸组MMP-9、MMP-2和PCNA表达明显降低.结论 microRNA-29a可以影响VSMC增殖和迁移,其机制可能是通过调节MMP-9、MMP-2和PCNA的表达来得以实现的.     

Mechanisms of vascular smooth muscle cell migration

Smooth muscle cell migration occurs during vascular development, in response to vascular injury, and during atherogenesis. Many proximal signals and signal transduction pathways activated during migration have been identified, as well as components of the cellular machinery that affect cell movement. In this review, a summary of promigratory and antimigratory molecules belonging to diverse chemical and functional families is presented, along with a summary of key signaling events mediating migration. Extracellular molecules that modulate migration include small biogenic amines, peptide growth factors, cytokines, extracellular matrix components, and drugs used in cardiovascular medicine. Promigratory stimuli activate signal transduction cascades that trigger remodeling of the cytoskeleton, change the adhesiveness of the cell to the matrix, and activate motor proteins. This review focuses on the signaling pathways and effector proteins regulated by promigratory and antimigratory molecules. Prominent pathways include phosphatidylinositol 3-kinases, calcium-dependent protein kinases, Rho-activated protein kinase, p21-activated protein kinases, LIM kinase, and mitogen-activated protein kinases. Important downstream targets include myosin II motors, actin capping and severing proteins, formins, profilin, cofilin, and the actin-related protein-2/3 complex. Actin filament remodeling, focal contact remodeling, and molecular motors are coordinated to cause cells to migrate along gradients of chemical cues, matrix adhesiveness, or matrix stiffness. The result is recruitment of cells to areas where the vessel wall is being remodeled. Vessel wall remodeling can be antagonized by common cardiovascular drugs that act in part by inhibiting vascular smooth muscle cell migration. Several therapeutically important drugs act by inhibiting cell cycle progression, which may reduce the population of migrating cells.     

Activation of vascular smooth muscle cells by TNF and PDGF: overlapping and complementary signal transduction mechanisms

OBJECTIVE: Because tumor necrosis factor-alpha (TNF) has been implicated in the pathogenesis of vein graft neointimal hyperplasia, we sought to determine mechanisms by which TNF could induce proliferative and migratory responses in smooth muscle cells (SMCs). METHODS AND RESULTS: In rabbit jugulocarotid interposition vein grafts, SMCs expressed TNF as early as four days postoperatively. In rabbit aortic SMCs, TNF and platelet-derived growth factor (PDGF) elicited comparable migration (1.7-fold/basal), and their effects were partially additive. In contrast, while TNF failed to promote SMC [(3)H]thymidine incorporation alone, it doubled the [(3)H]thymidine incorporation observed with PDGF alone. To gain mechanistic insight into these phenomena, we found that TNF and PDGF each activated p38(mapk) equivalently in SMCs, but that PDGF was two to three times more efficacious than TNF in activating SMC extracellular signal-regulated kinases (ERK) 1 and 2 and phosphoinositide 3-kinase. However, only TNF activated NF kappa B. SMC [(3)H]thymidine incorporation that depended on TNF, but not PDGF, was abolished by overexpression of a dominant-negative I kappa B alpha mutant. Inhibition of ERK activation by U0126 reduced SMC migration stimulated only by PDGF (by 35%, P<0.05), but not by TNF. Inhibition of phosphoinositide 3-kinase by LY294002, however, significantly reduced both TNF- and PDGF-stimulated chemotaxis (by 38-54%, P<0.05). In contrast, both U0126 and LY294002 abolished SMC [(3)H]thymidine incorporation induced by either TNF, PDGF, or both agonists. CONCLUSIONS: In primary rabbit SMCs, TNF promotes migration and mitogenesis through signaling mechanisms that are both distinct from and overlapping with those employed by PDGF. TNF-induced SMC mitogenesis requires complementary co-stimulation with other growth factors.     

Effects and related mechanism of quercetin on thrombin-induced proliferation and migration of rat vascular smooth muscle cells

<正>Objective To investigate the effects and related mechanism of quercetin on thrombin-induced proliferation and migration of rat vascular smooth muscle cells(VSMCs).Methods Third to fifth generation VSMCs were divided into three groups,including control group