Notch信号通路在婴儿血管瘤发病机制中的作用

婴儿血管瘤是婴幼儿最常见的良性肿瘤,目前有关婴儿血管瘤增殖和消退的机制尚未明确,仅局限于婴儿血管瘤形成的分子机制研究.多认为婴儿血管瘤的发生与血管内皮细胞异常增殖及碱性成纤维细胞生长因子、血管内皮细胞生长因子等细胞因子的异常表达有关.近年研究提示,Notch信号通路在婴儿血管瘤发生发展中发挥重要作用.Notch信号刺激血管内皮生长因子,通过调节血管内皮生长因子及其受体,调控血管内皮细胞增殖,参与婴儿血管瘤增生和退化.明确Notch信号在婴儿血管瘤发生机制中的作用,将为婴儿血管瘤提供合理的治疗方向.     

普萘洛尔治疗婴儿血管瘤的临床疗效及作用机制研究现状

婴儿血管瘤是常见的婴幼儿良性肿瘤,对于增生期的血管瘤应早期治疗,防止严重并发症的发生.普萘洛尔是临床常用的非选择性β肾上腺素受体阻滞剂.近年来,越来越多的研究报道普萘洛尔治疗婴儿血管瘤取得较好的疗效,其可能机制包括抑制血管内皮生长因子的生成、抑制低氧诱导性因子-1a-血管内皮生长因子-A血管发生轴、促使基质金属蛋白酶的下调、以及降低血管瘤的内皮一氧化氮合酶等.     

普萘洛尔治疗婴儿血管瘤的研究进展

【摘要】 普萘洛尔是非选择性β肾上腺素受体阻滞剂,多项研究已证实其治疗婴儿血管瘤安全有效,作用机制主要包括：①由周细胞介导的血流动力学改变及后续效应;②阻滞血管瘤来源的内皮细胞和干细胞的细胞周期进程从而抑制其增殖,诱导血管瘤来源的内皮细胞凋亡和血管瘤来源的干细胞向脂肪细胞分化;③抑制内皮祖细胞的募集;④降低促血管生成因子（如血管内皮生长因子、基质金属蛋白酶等）的水平。     

普萘洛尔治疗婴儿重症血管瘤的疗效及不良反应

血管瘤是最常见的婴儿良性肿瘤,重症血管瘤会引起严重的并发症,导致毁容、功能损害甚至危及生命.已有报道普萘洛尔(心得安)治疗重症血管瘤取得较好的疗效.普萘洛尔治疗血管瘤的机制包括收缩血管、抑制血管生成因子如血管内皮生长因子和碱性成纤维细胞生长因子表达,以及促进细胞凋亡.普萘洛尔作为一种非选择性的β-受体阻断剂,服用后可能引起低血压、心动过缓、低血糖、支气管痉挛等不良反应.因此服用时要严密监测生命体征.     

普萘洛尔治疗婴儿重症血管瘤的疗效及不良反应

血管瘤是最常见的婴儿良性肿瘤,重症血管瘤会引起严重的并发症,导致毁容、功能损害甚至危及生命.已有报道普萘洛尔(心得安)治疗重症血管瘤取得较好的疗效.普萘洛尔治疗血管瘤的机制包括收缩血管、抑制血管生成因子如血管内皮生长因子和碱性成纤维细胞生长因子表达,以及促进细胞凋亡.普萘洛尔作为一种非选择性的β-受体阻断剂,服用后可能引起低血压、心动过缓、低血糖、支气管痉挛等不良反应.因此服用时要严密监测生命体征.     

大麻素2型受体在银屑病分子免疫机制中的作用研究进展

银屑病是一种以鳞屑性红斑为主要临床表现的慢性、炎症性皮肤病。有研究表明银屑病皮损表皮中大麻素2型受体表达量明显增加,大麻素2型受体可参与细胞的增殖与分化、免疫调节以及肿瘤的发生发展等病理生理过程。在角质形成细胞中大麻素2型受体激活后可能通过Akt信号通路来抑制细胞的增殖,并且抑制炎症细胞分泌细胞因子,如血管内皮生长因子、基质金属蛋白酶、IL-8、IL-17等。本文就大麻素2型受体在银屑病分子免疫机制中的作用研究作一综述。     

HIF-VEGF-Notch信号通路在血管生成中的作用

血管生成(angiogenesis)是血管系统的一个重要分支,血管的生成发育参与某些生理与病理的发生发展.其复杂过程包含多种细胞因子、信号通路、基因调控等.本文就缺氧诱导因子-1α(HIF-1α)、血管内皮生长因子(VEGF)以及Notch信号通路在血管生成中的关系及作用进行了综述.     

血管内皮生长因子和皮肤肿瘤

血管内皮生长因子是一高度特异的血管内皮细胞有丝分裂原 ,最重要的促血管生长因子之一 ,调节生理性和病理性血管生成。血管内皮生长因子受体特异性地分布于血管内皮细胞表面 ,具有酪氨酸激酶活性。血管内皮生长因子及其受体在皮肤肿瘤中表达 ,并与皮肤肿瘤的发生、发展、转移以及判断皮肤肿瘤的良恶性有关 ,抑制血管内皮生长因子为皮肤肿瘤的治疗开辟新的途径     

血管内皮生长因子和皮肤肿瘤

血管内皮生长因子是一高度特异的血管内皮细胞有丝分裂原，最重要的促血管生长因子之一，调节生理性和病理性血管生成。血管内皮生长因子受体特异性地分布于血管内皮细胞表面，具有酪氨酸激酶活性。血管内皮生长因子及其受体在皮肤肿瘤中表达，并与皮肤肿瘤的发生、发展、转移以及判断皮肤肿瘤的良恶性有关，抑制血管内皮生长因子为皮肤肿瘤的治疗开辟新的途径。     

婴幼儿血管瘤发病机制研究进展

婴幼儿血管瘤(infantile hemangioma, IH)是一种常见的血管异常性疾病,目前对于IH的发病机制,尤其是自行消退的机制尚不十分清楚。研究发现血管瘤的内皮细胞与胎盘来源的血管内皮祖细胞具有同源性,遗传易感性、一些血管生成调节因子、细胞因子、转录因子、信号通路及基因在IH的发病机制中发挥着重要作用。本文就IH发病机制研究进展进行综述,以期为IH的治疗提供新的思路。。     

All-trans retinoic acid antagonizes UV-induced VEGF production and angiogenesis via the inhibition of ERK activation in human skin keratinocytes

Incident UV radiation leads to the upregulation of vascular endothelial growth factor (VEGF), a potent angiogenic factor, in human skin. However, the molecular basis of UV-induced angiogenesis in skin remains to be elucidated. In this study, we investigated the roles of UV exposure on cutaneous angiogenesis, its associated signaling mechanisms, and the effect of all-trans retinoic acid (tRA) on UV-induced vascularization, and VEGF expression. Using a human epidermal cell line, HaCaT, we found that UV induces VEGF mRNA and protein expression via the MAPK/ERK kinase-ERK1/2 (extracellular signal-regulated kinase 1/2) pathway but not via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, and that tRA pretreatment significantly inhibits UV-induced VEGF overexpression and ERK1/2 activation. In human skin in vivo, we confirmed that skin vascularization significantly increased after a single exposure to UV, as was evidenced by a prominent increase in vessel size, vascular density, and in the cutaneous area occupied by vessels, and we found that these events are associated with VEGF upregulation. Topical pretreatment with tRA under occlusion inhibited not only UV-induced VEGF upregulation and angiogenesis with a significant reduction of vessel density but also UV-induced ERK1/2 activation in human skin. Collectively, our data demonstrate that tRA inhibits the UV-induced angiogenic switch via downmodulation of ERK1/2 activation and consecutive VEGF overexpression. These findings may help us understand the molecular mechanisms that regulate skin angiogenesis due to UV exposure, and provide evidence of the potential of tRA in terms of preventing angiogenesis-associated skin damage following exposure to UV irradiation.     

Pharmacologic blockade of angiopoietin-2 is efficacious against model hemangiomas in mice

Hemangioma of infancy is the most common neoplasm of childhood. While hemangiomas are classic examples of angiogenesis, the angiogenic factors responsible for hemangiomas are not fully understood. Previously, we demonstrated that malignant endothelial tumors arise in the setting of autocrine loops involving vascular endothelial growth factor (VEGF) and its major mitogenic receptor vascular endothelial growth factor receptor 2. Hemangiomas of infancy differ from malignant endothelial tumors in that they usually regress, or can be induced to regress by pharmacologic means, suggesting that angiogenesis in hemangiomas differs fundamentally from that of malignant endothelial tumors. Here, we demonstrate constitutive activation of the endothelial tie-2 receptor in human hemangioma of infancy and, using a murine model of hemangioma, bEnd.3 cells; we show that bEnd.3 hemangiomas produce both angiopoietin-2 (ang-2) and its receptor, tie-2, in vivo. We also demonstrate that inhibition of tie-2 signaling with a soluble tie-2 receptor decreases bEnd.3 hemangioma growth in vivo. The efficacy of tie-2 blockade suggests that either tie-2 activation or ang-2 may be required for in vivo growth. To address this issue, we used tie-2-deficient bEnd.3 hemangioma cells, which, surprisingly, were fully proficient in in vivo growth. Previous studies from our laboratory and others have implicated reactive oxygen-generating nox enzymes in the angiogenic switch, so we examined the effect of nox inhibitors on ang-2 production in vitro and on bEnd.3 tumor growth in vivo. We then inhibited ang-2 production pharmacologically using novel inhibitors of nox enzymes and found that this treatment nearly abolished bEnd.3 hemangioma growth in vivo. Signal-transduction blockade targeting ang-2 production may be useful in the treatment of human hemangiomas in vivo.     

Overproduction of VEGF concomitantly expressed with its receptors promotes growth and survival of melanoma cells through MAPK and PI3K signaling

Vascular endothelial growth factor (VEGF) is an important mediator of tumor-associated angiogenesis, and consequently it has been associated with metastasis. We report here that the overexpression of VEGF(165) in melanoma xenografts promotes an acceleration of tumor growth and an increase in angiogenesis as well as the spontaneous metastasis formation. In addition, VEGF receptors (VEGFR)1, VEGFR2 and neurophilin-1 are expressed in A375 melanoma cells. Forced overexpression of VEGF in these cells induces cell growth and triggers survival activity in serum-starved cultures, by a mechanism dependent on the mitogen-activating protein kinase signaling pathway. Furthermore, these effects are dependent MEK 1/2 activity. Kinase domain region-specific tyrosine kinase inhibitors dramatically reduced DNA synthesis to 20% with respect to the controls, although they did not completely suppress either the p44 or p42-phosphorylated forms of extracellular signal-regulated protein kinase. These inhibitors also provoked a decrease in Akt phosphorylation. We observed a dramatic reduction in survival after treatment with phosphatidylinositol 3'-kinase (PI3K)-specific inhibitor in the presence of specific tyrosinase inhibitors. We suggest that the overproduction of VEGF(165) concomitantly expressed with its receptors favors cell growth and survival of melanoma cells through MAPK and PI3K signaling pathways. These data support the involvement in melanoma growth and survival of a VEGF-dependent internal autocrine loop mechanism, at least in vitro.     

The genetics of vascular birthmarks

One in 10 infants are born with a vascular birthmark each year. Some vascular birthmarks, such as infantile hemangiomas, are common, while vascular malformations, such as capillary, lymphatic, venous, and arteriovenous malformations, are less so. Diagnosing uncommon vascular birthmarks can be challenging, given the phenotypic heterogeneity and overlap among these lesions. Both sporadic and germline variants have been detected in various genes associated with vascular birthmarks. Identification of these genetic variants offers insight into both diagnosis and underlying molecular pathways and can be fundamental in the discovery of novel therapeutic approaches. The PIK3/AKT/mTOR and RAS/MEK/ERK signaling pathways, which mediate cell growth and angiogenesis, are activated secondary to genetic variations in vascular malformations. Somatic variants in TEK (TIE2) and PIK3CA cause venous malformations. Variants in PIK3CA also cause lymphatic malformations as well as a number of overgrowth syndromes associated with vascular anomalies. Variants in GNAQ and GNA11 have been identified in both so-called “congenital” hemangiomas and capillary malformations. RASA1 and EPHB4 variants are associated with capillary malformation-arteriovenous malformation syndrome. This review discusses the genetics of vascular birthmarks, including the various phenotypes, genetic variants, pathogenesis, associated syndromes, and new diagnostic techniques.     

VEGF bFGF C-myc在婴幼儿皮肤血管瘤中的作用及相关性

目的　探讨VEGF、bFGF、C- myc在婴幼儿血管瘤发生发展中的作用及相关性。方法　采用免疫组化S P法检测 32例增生期和 38例消退期血管瘤组织中VEGF、bFGF、C- myc。结果　VEGF、bFGF在增生期血管瘤中的阳性率均为 100%,而在消退期血管瘤中的阳性率分别为 73. 68%, 84. 21%,两组之间差异有显著性 (P均 <0. 01)。C -myc在消退期血管瘤中的阳性率为 100%,明显高于增生期血管瘤 81. 25%,两组之间差异有显著性 (P<0. 01)。Spearman相关分析,VEGF与bFGF在增生期和消退期血管瘤中呈正相关(rs=0.523,P<0.01; rs=0.541,P<0. 01),而C -myc和VEGF在增生期和消退期血管瘤中呈负相关(rs=-0.413,P<0.05;rs=-0.472,P<0. 01)。C- myc与bFGF在增生期血管瘤中呈负相关(rs=-0.475,P<0. 01),在消退期血管瘤中无相关性(rs=-0.229,P>0. 05)。结论　VEGF,bFGF,C- myc在婴幼儿皮肤血管瘤发生、发展中起着重要作用,VEGF,bFGF共同促进血管瘤增生,而C- myc与血管瘤增生、消退有关。     

Prolonged growth of infantile hemangioma after pulsed dye laser and oral propranolol treatment

Infantile hemangiomas are the most common tumor of childhood and undergo rapid growth during early infancy followed by gradual involution. After involution, residual lesions sometimes remain. Oral propranolol usually induces earlier involution and redness reduction of infantile hemangiomas. However, the optimal treatment duration is unknown and infantile hemangiomas sometimes recur after cessation of treatment. We report three Japanese patients with recurrent infantile hemangiomas on their cheek. These patients were a 1‐month‐old female baby with a superficial infantile hemangioma, a 3‐month‐old female baby with a mixed infantile hemangioma and a 4‐month‐old male baby with a mixed infantile hemangioma. Two of them also received pulsed dye laser treatment. They did not reach complete or nearly complete resolution of infantile hemangiomas at week 25. These patients experienced regrowth of their infantile hemangioma after 20 months of age and took propranolol after the age of 24 months. There were no severe adverse effects. Propranolol may not only be therapeutic but also prophylactic. Patients with infantile hemangiomas who have taken oral propranolol should be followed up at least 6 months after cessation of treatment, especially infantile hemangiomas on the cheek, and those with partial response to propranolol may require close attention in prolonged growth.     

Oncogenes and angiogenesis: signaling three-dimensional tumor growth

Three-dimensional tumor growth is dependent on the perpetual recruitment of host blood vessels to the tumor site. This recruitment process (mainly via angiogenesis) is thought to be triggered, at least in part, by the very same set of genetic alterations (activated oncogenes, inactivated/lost tumor suppressor genes) as those responsible for other aspects of malignant transformation (e.g., aberrant mitogenesis, resistance to apoptosis). Potent oncogenes are able to deregulate expression of both angiogenesis stimulators and inhibitors in cancer cells. For example, mutant ras expression is associated with increased production of vascular endothelial growth factor (VEGF) and downregulation of thrombospondin-1 (TSP-1). Upregulation of VEGF and angiogenesis can also be induced by constitutive activation of other oncogenic proteins (e.g., EGFR, Raf, MEK, PI3K) acting at various levels on the Ras signaling pathway. The mode and the magnitude of such proangiogenic influences can be significantly modified by cell type (fibroblastic or epithelial origin), epigenetic factors (hypoxia, changes in cell density), and/or presence of additional genetic lesions (e.g., preceding loss of p16 or p53 tumor suppressor genes). Activated oncogenes (e.g., ras, src, HER-2) induce co-expression of angiogenic properties concomitantly with several highly selectable traits (increased mitogenesis, resistance to apoptosis), a circumstance that may accelerate selection of the angiogenic phenotype at the cell population level. On the other hand oncogene-induced reduction in growth requirements may also endow tumor cells with a diminished (albeit not abrogated) dependence on (close) proximity to blood vessels, i.e., with reduced vascular dependence. Thus, oncogenes can impact several interconnected aspects of cellular growth, survival, and angiogenesis. Experimental evidence suggests that, in principle, many of these properties (including angiogenesis) can be simultaneously suppressed (and tumor stasis or regression induced) by effective use of the specific oncogene antagonists and signal transduction inhibitors.     

婴儿血管瘤治疗的新认识

婴儿血管瘤是儿童时期最常见的良性肿瘤,具有自然退化的特性,容易出现并发症或后遗症的患儿需要积极治疗.为此,概述了婴儿血管是否需要接受治疗的3个预测因素:血管瘤的大小、血管瘤发生的解剖学位置和血管瘤的形态学亚型,以及介绍系统或局部应用糖皮质激素、皮损内注射糖皮质激素、激光或手术治疗,以及近年来应用β受体阻滞剂治疗婴儿血管瘤等的治疗方法,以期能加深临床工作者对婴儿血管瘤治疗方法的认识,进一步进行临床研究.