CD146对子宫内膜异位症新生血管形成的潜在作用

子宫内膜异位症(endometriosis,EMs)已经成为全球瞩目的公共卫生问题,是严重影响育龄期妇女生活质量的疾病之一。新生血管形成是EMs病灶形成的必备条件。CD146不仅参与炎症调节,近年研究发现CD146还参与肿瘤的新生血管形成。有研究表明,EMs患者异位病灶的CD146较在位内膜中表达升高,提示CD146可能参与EMs的发生发展,但确切的机制尚不明确。就新生血管形成方面,CD146的异常表达对EMs的发生发展可能发挥重要作用。表达在间充质干细胞(MSCs)表面的CD146可以促进MSCs向血管平滑肌细胞(VSMC)系分化、可溶性CD146(sCD146)与血管抑素结合蛋白结合上调磷酸化黏着斑激酶(p-FAK),磷酸化蛋白激酶B(p-AKT),磷酸化应激活化蛋白激酶(pJNK)促进内皮细胞的增殖和迁移,CD146亦可与血管内皮生长因子受体2(VEGFR-2)形成共受体增强血管内皮生长因子(VEGF)激活的信号转导,促进新生血管形成;CD146作为成纤维细胞生长因子(FGF)受体促进内皮细胞的增殖、迁移;亦可与血小板衍生生长因子受体β(PDGFR-β)形成共受体促进血管管状结构的形成。     

信号通路调控子宫内膜异位症的研究进展

子宫内膜异位症（EMs）是育龄妇女中的常见病、疑难病,发病机制错综复杂,极具侵袭性,易转移和复发,治疗效果不甚满意,而针对其发生发展机制的研究,寻找有效治疗方法是目前妇科领域研究的焦点。近年来研究发现,异位内膜细胞的上皮间质转化、黏附侵袭和血管生成过程是EMs发生发展中的重要机制,在此过程中有多条信号通路的调控,如转化生长因子β（TGF-β）/Smad、Notch、核因子κB（NF-κB）、Wnt/β连环蛋白（β-catenin）、磷脂酰肌醇3激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（PI3K/Akt/mTOR）。阐述EMs发病过程中涉及的相关信号通路研究,为临床防治EMs提供新的思路。     

趋化因子及其受体在子宫内膜异位症发病中的作用

子宫内膜异位症（EMs）发病机制复杂,近年免疫学概念的引入对深入理解EMs发病机制产生了重要影响。趋化因子及受体在EMs的发生和发展中起重要作用。EMs患者腹腔内多种趋化因子及受体表达水平升高,其异常表达可能招募免疫细胞进入腹腔,促进腹腔炎症反应,并通过分泌细胞因子及促进内膜的黏附、侵袭及新生血管生成等复杂机制促进EMs的形成。     

血管内皮细胞生长因子与子宫内膜异位症

血管内皮细胞生长因子（VEGF）是一种特异地作用于血管内皮细胞的多功能细胞因子，与内皮细胞上的激酶插入嵌合受体/胎肝激酶1（KDR/Flk-1）和fms样酪氨酸激酶（Flt-1）受体高亲和力地结合，作为内皮细胞特异性有丝分裂原，诱导内皮细胞增生及毛细血管袢形成，同时诱导间质产生，促进体内新血管生成。针对这一机制，减少VEGF的产生，降低VEGF的生物学活性，阻断其与受体结合，可为子宫内膜异位症（EMs）的治疗开辟新途径。     

巨噬细胞在子宫内膜异位症神经纤维及血管生成中的作用及机制

子宫内膜异位症（endometriosis,EMs）是育龄期女性常见疾病,其发病机制目前尚未明确,其中神经纤维及血管生成是促进疾病进展、产生慢性盆腔痛及子宫内膜异位病灶增大的重要机制,而其形成原因亦非常复杂,很可能与EMs免疫微环境的改变密切相关。而作为EMs免疫因素重要成分的巨噬细胞,在疾病发生、发展中异常募集并产生表型及功能的改变,分泌多种促炎及抗炎细胞因子,引起神经信号的过度兴奋和通路转导异常,并参与血管内皮生长因子（VEGF）通路的调控,对神经血管的生成有重要作用。总结在EMs中巨噬细胞表型功能变化对神经纤维异常生成及盆腹腔中血管增生的作用及其潜在机制,为针对巨噬细胞与EMs神经血管生成的靶向治疗可以干预炎症过程、周围神经和血管的生成提供理论支持,为解析EMs的发病机制提供新的思路。     

子宫内膜异位症相关信号通路研究进展

子宫内膜异位症（EMs）作为妇科公认的疑难病,严重影响女性身心健康,因其病变多态性、侵袭性、广泛性,其发病机制目前尚无统一定论。相关信号通路的异常激活、多细胞因子的共同作用均会导致异位内膜细胞黏附、侵袭以及炎症的形成,目前丝裂原活化蛋白激酶（MAPKs）、Wnt/β-连环蛋白（β-catenin）、转化生长因子β（TGF-β）/Smad、核因子κB（NF-κB）、Ras同源基因/Rho相关螺旋卷曲蛋白激酶（Rho/ROCK）、Janus激酶2/转录活化因子3（JAK2/STAT3）等信号通路与EMs的发生、发展密切相关。现从以上6条通路阐述EMs的发病机制,为其寻找有效靶向药物治疗提供新的思路。     

趋化因子及其受体在子宫内膜异位症发病中的作用

子宫内膜异位症(EMs)发病机制复杂,近年免疫学概念的引入对深入理解EMs发病机制产生了重要影响.趋化因子及受体在EMs的发生和发展中起重要作用.EMs患者腹腔内多种趋化因子及受体表达水平升高,其异常表达可能招募免疫细胞进入腹腔,促进腹腔炎症反应,并通过分泌细胞因子及促进内膜的黏附、侵袭及新生血管生成等复杂机制促进EMs的形成.     

血管生成因子在子宫内膜异位症中的研究进展

近年来研究表明，血管生成因子（EGF、FGF、TGF、TNF、IL－8及VEGF）与EMs的关系密切，它们要以刺激血管内皮细胞生长和体内新生血管形成，通过自分泌与旁分泌方式调控异位病灶的种植与发展，在EMs的发病机制中起重要作用，对这些因子的深研究将为寻求EMs新治疗方法提供帮助。     

内皮祖细胞在子宫内膜异位症血管形成中的研究进展

子宫内膜异位症（endometriosis,EMs）是一种复杂的多病因妇科疾病,EMs的发生、发展依赖于血管新生（neovascularization）。EMs的血管新生包括血管生成（angiogenesis）和血管形成（vasculogenesis）。血管形成是由循环中的内皮祖细胞（endothelial progenitor cell,EPC）参与的,此过程包括骨髓来源的EPC活化、动员和向外周组织的募集。除EMs外,血管形成还是肿瘤、动脉硬化等多种疾病的特征性病理变化。研究表明部分 EMs病灶微血管内皮细胞是由EPC分化而来的,基质细胞衍生因子1（SDF-1）/CXC趋化因子受体4（CXCR4）轴参与了外周组织对EPC募集的调控,阻断EPC募集能有效地抑制异位病灶微血管的形成。抑制异位内膜中EPC介导的血管形成有望成为EMs抗血管治疗新的切入点。     

Toll样受体与子宫内膜及子宫内膜异位症

子宫内膜异位症（EMs）发病机制尚未完全阐明。大量研究表明,免疫因素在EMs的发病机制中起重要作用。EMs免疫应答异常主要是巨噬细胞数量和活性增加及其分泌产物,如生长因子、细胞因子和血管生成因子的改变。Toll样受体（TLRs）识别特异性的病原体相关分子模式,启动和介导免疫应答,在固有免疫中发挥重要作用,并诱导产生适应性免疫反应。TLRs在正常子宫内膜中的生理作用以及在EMs中的相关研究已逐步开展,对其深入认识和研究将为EMs诊断、治疗和预后判断提供新思路和手段。     

Effect of monocyte chemoattractant protein-1 and estradiol on the secretion of vascular endothelial growth factor in endometrial stromal cells in vitro

To explore the initial activity of endometrial stromal cells (ESCs) and the participation of monocyte chemoattractant protein-1 (MCP-1) in the histogenesis of endometriosis, vascular endothelial growth factor (VEGF) secretion of ESCs and the effect of MCP-1 on VEGF secretion of ESCs were observed in vitro. The VEGF level was detected in ESC culture media and was increased significantly when E2 or MCP-1 was added to the media, especially in the presence of E2 plus MCP-1. The VEGF secretion was higher in the ESCs of women with endometriosis than in those women without endometriosis.     

Intercellular adhesion molecule-1 and hepatocyte growth factor in human endometriosis: original investigation and a review of literature

Defects in the cell-mediated immune system may play a role in the pathogenesis or progression of pelvic endometriosis. Possible mediators include macrophages, interleukins-1 and -6, and tumor necrosis factor-alpha. More recent work points to the involvement of adhesion molecules and growth factors. To clarify the pathogenesis of endometriosis, we compared the characteristics of soluble intercellular adhesion molecule-1 (soluble ICAM-1) and hepatocyte growth factor (HGF) in women with and without endometriosis. We found that, in patients with endometriosis, the concentrations of soluble ICAM-1 in peritoneal fluid increased and interfered with the activity of natural killer cells. We also found that HGF secretion was significantly increased in cultured endometrial stromal cells, and that HGF stimulated the proliferation and migration of, and morphogenic changes in, endometrial epithelial cells. HGF and ICAM-1 play important roles in the initiation and regulation of endometriotic lesions on the microenvironment level. The increased secretion of HGF by eutopic endometrial stromal cells may contribute to the pathogenesis of endometriosis, whereas the increased levels of soluble ICAM-1 may impair natural killer cell activity and accelerate the progression of the disease.     

Effect of vascular endothelial growth factor inhibition on endometrial implant development in a murine model of endometriosis

The main factor involved in neovascularization of ectopic endometrial tissue in endometriosis is the vascular endothelial growth factor (VEGF), which is produced both by the endometrial implant and by peritoneal macrophages. On the other hand, bevacizumab is an antiangiogenic agent used in the treatment of different tumors, like colorectal, pulmonary, and recently mammary. We evaluated the effect of the inhibition of VEGF activity with bevacizumab (Avastin) on ectopic endometrial growth in a murine model of endometriosis. Two months old female BALB/c mice had surgery performed to induce endometriotic-like lesions. Treatment with bevacizumab started on post-surgery day 15 and continued during 2 weeks. Then, animals were sacrificed, peritoneal fluid was collected, and endometriotic-like lesions were counted, measured, and removed. Cell proliferation, vascular density, and apoptosis were assessed by immunohistochemistry for proliferating cell nuclear antigen (PCNA), immunohistochemistry for CD34, and Terminal Deoxynucleotidil Transferase-Mediated dUTP Nick End Labeling (TUNEL), respectively. Vascular endothelial growth factor levels were evaluated in the peritoneal fluid by enzyme-linked immunoassay (ELISA). Treatment with bevacizumab significantly inhibited endometriotic lesion development (P < .05). Consistently, bevacizumab significantly inhibited cell proliferation in lesions (P < .01), reduced vascular density (P < .001), as well as increased the apoptotic cell percentage (P < .001). In addition, bevacizumab reduced VEGF levels in peritoneal fluid of endometriosis-induced animals (P < .05). In conclusion, this study suggests a direct effect of bevacizumab on the reduction of endometrial implant growth and supports further research on VEGF inhibition as a novel therapeutic modality in endometriosis.     

Marked elevation of macrophage migration inhibitory factor in the peritoneal fluid of women with endometriosis

OBJECTIVE: To evaluate the presence of macrophage migration inhibitory factor (MIF) in the peritoneal fluid of normal fertile women and patients with endometriosis and its growth-promoting activity toward human endothelial cells. DESIGN: Retrospective study using ELISA to measure peritoneal fluid MIF, and [3H]-thymidine incorporation into the DNA of human endothelial cells to assess its mitogenic activity. SETTING: Gynecology clinic and human reproduction research laboratory. PATIENT(S): Thirty-six healthy women and 57 women with endometriosis. INTERVENTION(S): Peritoneal fluid samples were obtained at laparoscopy. MAIN OUTCOME MEASURE(S): Macrophage migration inhibitory factor concentrations in the peritoneal fluid samples and [3H]-thymidine incorporation into the DNA of human microvascular endothelial cells to assess proliferation. RESULT(S): This study demonstrated the presence of MIF in the peritoneal fluid and a 238% increase of MIF levels in women with endometriosis as compared with healthy women. Both fertile and infertile women with endometriosis had significantly higher MIF concentrations than did fertile women with normal gynecological status, but the difference was more significant in infertile endometriosis patients. Anti-MIF antibody significantly inhibited proliferation of human microvascular endothelial cells in response to peritoneal fluids from healthy women and women with endometriosis stages I-II and III-IV, as assessed by [3H]-thymidine incorporation. CONCLUSION(S): This study revealed the presence of MIF in the peritoneal fluid and its increased levels in endometriosis and suggests that MIF may be involved in endometriosis-associated infertility and angiogenesis.     

凶险性前置胎盘组织中HMGB1蛋白表达及其与胎盘植入的关系研究

目的:探讨凶险性前置胎盘组织中高迁移族蛋白B1(HMGB1)的表达及其与合并胎盘植入的关系。方法:收集本院凶险性前置胎盘孕妇68例(凶险性前置胎盘组),其中合并胎盘植入组21例,未合并胎盘植入组47例,另选同期非前置胎盘剖宫产孕产妇40例作为对照组。采用免疫组织化学法检测两组胎盘组织中HMGB1和血管内皮生长因子(VEGF)的表达,并计数胎盘中微血管密度(MVD);采用蛋白免疫印迹分析胎盘组织中HMGB1和VEGF蛋白表达量。结果:两组胎盘组织中HMGB1和VEGF蛋白表达均定位于血管内皮细胞。凶险性前置胎盘组HMGB1、VEGF和MVD水平均显著高于对照组,且合并植入组HMGB1、VEGF、MVD均显著高于未合并植入组(P<0.05)。凶险性前置胎盘中HMGB1蛋白表达量与MVD值呈明显正相关(r=0.345,P<0.05),与胎盘VEGF表达量呈明显正相关(r=0.250,P<0.05),且VEGF与MVD值呈明显正相关(r=0.252,P<0.05)。结论:凶险性前置胎盘组织中存在HMGB1高表达,且与胎盘植入发生相关,其机制可能为通过促进VEGF表达参与胎盘的血管生成过程。     

The role of prostaglandin E2 in endometriosis

Endometriosis is a leading cause of infertility in women of reproductive age. It involves the occurrence of endometrial tissue outside the uterine endometrium, mainly in the peritoneal cavity. Prostaglandin E(2) is up regulated in the peritoneal cavity in endometriosis and is produced by macrophages and ectopic endometrial cells. This prostaglandin is involved in the pathophysiology of the disease and elicits cell signals via four receptor types. Prostaglandin E(2) increases estrogen synthesis by up regulating steroidogenic acute regulatory protein (StAR) and aromatase. It inhibits apoptosis and up regulates fibroblast growth factor-9 (FGF-9) promoting cell proliferation. Prostaglandin E(2) affects leukocyte populations and promotes angiogenesis through its effect on estrogen and up regulation of vascular endothelial growth factor (VEGF). Dienogest is a synthetic progestin targeting expression of genes involved in prostaglandin synthesis.     

New insights into the pathophysiology of endometriosis

Endometriosis is a fascinating and complex disease resulting from a dysregulation between exfoliated menstrual endometrium and the intra-abdominal environment. Increased concentrations of activated pelvic macrophages and lymphocytes and elevated levels of specific cytokines and growth factors in the peritoneal fluid support this hypothesis. The precise roles of these soluble factors are currently unknown, but we propose that a complex interplay of these locally produced cytokines, growth factors, steroids and eicosanoids modulates the growth and inflammatory behavior of ectopic endometrial implants via neovascularization. The enhanced secretion of local proangiogenic proteins by endometriosis lesions and associated immune cells (and the concomitant reduction of antiangiogenic principles) promotes the recruitment of capillaries toward the growing lesions. Ultimately, a cascade of effects on the peritoneal microenvironment results in implant proliferation and invasion. Future therapeutic strategies to target these angiogenic stimuli have the potential to block the vascular pathogenesis of endometriosis. This article gives an overview of the different factors involved in the development, growth and progression of endometriosis.     

sFlt-1及PLGF与子痫前期发病的关系

可溶性血管内皮生长因子受体1 (sFlt-1)与Flt-1均属于血管内皮生长因子受体(VEGFR),其与Flt-1竞争结合VEGF,完全阻断VEGF的生物学活性,引起血管生成障碍并影响血管壁的完整性和通透性.胎盘生长因子(PLGF)是VEGF家族成员之一,PLGF与Flt-1受体结合时,发挥促血管生成和促绒毛滋养细胞增...     

The role of GnRH analogues in endometriosis-associated apoptosis and angiogenesis

It has been postulated that gonadotropin-releasing hormone (GnRH) analogues may act directly on endometrial cells and inhibit their growth and proliferation by regulation of apoptotic and angiogenic mechanisms. Eutopic endometrial cells from patients with endometriosis show an increased proliferation rate and are less susceptible to cell death by apoptosis than those from subjects without the disease. Notably, the GnRH analogue, leuprorelin, inhibits cell proliferation and increases the apoptotic rate in eutopic endometrial cell cultures, an effect that appears to be mediated by an increase in the expression of the pro-apoptotic proteins Bax and FasL and a decrease in the expression of the anti-apoptotic protein Bcl-2. Angiogenesis is an important process in the development of endometrial tissue, and it is regulated by vascular endothelial growth factors (VEGFs) and angiopoietins. VEGF levels are elevated in peritoneal fluid and endometriotic tissue from patients with endometriosis. In addition, it has been demonstrated that the expression of VEGF is potentiated by a variety of cytokines, including IL-1beta. Recent studies show that leuprorelin reduces the production of VEGF-A and IL-1beta in eutopic endometrial cell cultures, suggesting a mechanism by which it could inhibit the development of endometriosis. Thus, GnRH analogues appear to be effective in reducing the growth of endometrial cells, not only due to their classical pituitary endocrine effects, but also via a direct effect on the endometrial cells themselves.     

Activation of invasiveness of cervical carcinoma cells by angiotensin II

OBJECTIVE: Angiotensin II recently has been reported to promote the growth of several kinds of cells. In this study, we investigated the effect of angiotensin II on cervical carcinoma cells. STUDY DESIGN: The expression of angiotensin II type I receptor was examined by immunohistochemistry in normal and neoplastic cervical tissues. Invasion assay was examined in Siha cells (cervical squamous cell carcinoma) and vascular endothelial growth factor levels were assayed with a vascular endothelial growth factor enzyme-linked immunosorbent assay kit. RESULTS: Mean staining intensity level was stronger in invasive carcinoma cells than in normal, dysplasia, and carcinoma in situ tissues. Angiotensin II induced the secretion of vascular endothelial growth factor from Siha cells. Furthermore, angiotensin II promoted the invasive potential of Siha cells. These effects were reversed by the addition of anti-human vascular endothelial growth factor antibody and candesartan (antagonist of angiotensin II type I receptor). CONCLUSION: Angiotensin II is involved in the progression of cervical carcinoma, because it induces the secretion of vascular endothelial growth factor through angiotensin II type I receptor, which results in the increased invasiveness of carcinoma cells.