VEGF相关信号通路在血管新生中的研究进展

组织器官在生理或病理状态下,受到促血管生成因子的刺激,引发生血管新生。VEGF、Notch、Wnt/β-catenin、Ang1(2)/tie2、PI3K-AKT等多个信号通路参与到该过程,对血管新生的各个阶段产生影响。其中VEGF联系众多信号通路,对血管新生整个过程进行调节,发挥了无可替代的作用。近年来国内外对VEGF及相关信号通路调节血管新生机制的研究取得了一定的进展,对多种疾病发病机制的阐明及临床药物的研发提供了新的理论依据。我们总结了近年来相关研究成果,希望为血管新生相关疾病的治疗提供新的可能性。     

玻璃体腔注射雷珠单抗治疗渗出型老年性黄斑变性伴浆液性视网膜色素上皮脱离的疗效观察

目的 观察玻璃体腔注射雷珠单抗(IVR)治疗渗出型老年性黄斑变性(AMD)伴浆液性视网膜色素上皮脱离(PED)的临床效果.方法 临床确诊为渗出型AMD伴浆液性PED并行IVR治疗的23例患者23只眼纳入研究.所有患者采用国际标准对数视力表行最佳矫正视力(BCVA)检查,检测结果转换为最小分辨角对数(logMAR)记录;并采用光相干断层扫描(OCT)检查测量PED高度、PED容积及黄斑中心凹视网膜厚度(CFT).患眼平均logMAR BCVA为0.77±0.39,平均PED高度为(357.2±171.9) μm,平均PED容积为(0.741±1.012) mm3,平均CFT为(317.9±73.8)μm.治疗方法为手术室无菌条件下常规玻璃体腔注射10 mg/ml的雷珠单抗0.05 ml(含雷珠单抗0.5 mg),每一个月注射1次,连续注射3次,此后根据随访情况按需注射.以末次治疗后6个月为疗效判定时间点,对比分析治疗前后患眼BCVA、PED高度、PED容积及CFT变化情况.结果 治疗后患眼平均logMAR BCVA为0.61±0.27,较治疗前明显提高,差异有统计学意义(t=2.601,P＜0.05).23只眼中,视力提高17只眼,视力稳定4只眼,视力下降2只眼.治疗后患眼平均PED高度为(247.7±171.7)μm,平均PED容积为(0.337±0.498) mm3,平均CFT为(302.5±89.3) μm.与治疗前比较,治疗后患眼平均PED高度、平均PED容积均明显减小,差异有统计学意义(t=3.192、2.502,P＜0.05);平均CFT有所降低,但差异无统计学意义(t=0.887,P＞0.05).所有患者在随访期内均未发生眼内炎、葡萄膜炎等眼部不良反应.结论 IVR能安全有效地治疗伴有浆液性PED的渗出型AMD,提高患者视力,降低PED高度,减小PED容积.     

玻璃体腔重复注射雷珠单抗对脉络膜新生血管患眼脉络膜厚度的影响

目的 观察玻璃体腔重复注射雷珠单抗对脉络膜新生血管(CNV)患眼脉络膜厚度(CT)的影响.方法 前瞻性、开放性无对照研究.临床确诊的渗出型老年性黄斑变性(AMD)患者31例31只眼(AMD组)以及病理性近视CNV患者33例33只眼(病理性近视组)纳入研究.所有患眼行玻璃体腔注射10 mg/ml的雷珠单抗0.05 ml(含雷珠单抗0.5 mg)治疗,之后每一个月随访1次,共随访6个月.AMD组、病理性近视组患眼平均注射次数分别为(4.23±1.33)、(2.27±0.88)次.治疗前及治疗后1、3、6个月,采用频域光相干断层扫描的增强深度成像技术测量患眼中心凹下CT.对比分析治疗前后患眼的CT变化.分析末次随访时CT降低值与注射次数的相关性.结果 治疗后l、3、6个月,AMD组患眼平均CT较治疗前分别降低了(9.68±11.02)、(12.58±11.04)、(13.84±11.67) μm.AMD组患眼治疗后1、3、6个月平均CT与治疗前比较,差异均有统计学意义(t=4.89、6.34、6.60,P＜0.001).病理性近视组患眼平均CT分别为(81.09±63.20)、(79.52±63.64)、(79.88±62.46) μm,较治疗前分别降低了(2.06±10.92)、(3.64±8.78)、(3.27±7.20)μm.病理性近视组患眼治疗后1个月平均CT与治疗前比较,差异无统计学意义(t=1.08,P=0.287);治疗后3、6个月平均CT与治疗前比较,差异均有统计学意义(t=2.38、2.61,P=0.024、0.014).相关性分析结果显示,AMD组、病理性近视组患眼末次随访时CT降低值与注射次数均无相关性(r=0.04、0.30,P=0.815、0.099).结论 玻璃体腔重复注射雷珠单抗会引起渗出型AMD及病理性近视CNV患眼的CT降低.     

Bisphenol A promotes X‐linked inhibitor of apoptosis protein‐dependent angiogenesis via G protein‐coupled estrogen receptor pathway

Bisphenol A (BPA), one of the high‐volume chemicals worldwide, has a core structure resembling that of natural estradiol. Recent evidence has demonstrated that exposure to BPA has a relationship with the risk of cancer. The objective of our study is to investigate the mechanisms underlying the pro‐angiogenic effects of BPA. We demonstrated that BPA markedly induces endothelial cell proliferation, migration and tube formation by activating endothelial nitric oxide synthase. BPA‐induced nitric oxide generation appeared to be associated with the X‐linked inhibitor of apoptosis protein (XIAP), which competes with endothelial nitric oxide synthase for caveolin‐1. BPA was shown to exert its pro‐angiogenic effect by upregulating XIAP expression via G protein‐coupled estrogen receptor (ER) activation but not via ERα or ERβ. Our data suggest that 100 nM BPA promote angiogenesis in a G protein‐coupled ER‐dependent genomic pathway, and provide a novel insight into the potential role of XIAP in mediating the pro‐angiogenic effects of BPA in endothelial cells. Copyright © 2015 John Wiley & Sons, Ltd.     

Elevated serum endostatin levels is associated with favorable outcome in acute myeloid leukemia

Introduction

Endostatin is the C-terminal antiangiogenic fragment of the extracellular matrix protein collagen XVIII, and is generated by tumor-derived proteases. The levels and the prognostic relevance of serum endostatin in AML patient is not fully clear.

Aim

To evaluate serum levels of endostatin in acute myeloid leukemia patients before chemotherapy and after achieving complete remission and to correlate endostatin levels with patients outcome.

Materials and methods

Serum samples from 30 adult patients (22 males and 8 females, median age 37, range 19–66 years) with AML had been taken before chemotherapy was administered. In addition 20 out of 30 patients were reinvestigated again at complete remission (CR). Ten samples from healthy normal persons of matched age and sex were evaluated as a reference control group. Serum endostatin levels were determined using enzyme linked immune sorbent assay (ELISA).

Results

Endostatin serum levels were not significantly different in the pretreatment AML patients as compared to that in normal controls (P>0.05). In AML patients the baseline endostatin levels were significantly lower than at CR (P=0.001). No significant correlation were detected between pretreatment serum endostatin levels and age, peripheral blood white cell counts, platelet counts, bone marrow blast cell counts, blast cell distribution ratio. The prognostic value of sE was also evaluated by dividing AML patients into high and low sE groups using the 75 percentile sE levels of the patients group as cutoff. The authors found that patients group in the high sE group survived for significantly longer time than those patients in the low sE group.

Conclusions

Elevated endostatin levels at AML diagnosis is a good prognostic marker for patients’ outcome. Wide scale study is recommended in order to establish the clinical value of this study.

     

VEGF在大鼠心肌梗死急性期表达的意义及蜕皮甾酮的促侧支循环作用

目的以急性心肌梗死大鼠为模型,观察血管内皮生长因子(VEGF)在心肌中的表达,探讨急性缺血缺氧刺激与VEGF产生的关系和意义以及蜕皮甾酮(EDS ecdysterone)的促侧支循环作用.方法建立Wistar大鼠急性心肌梗死模型,分为对照组、急性心肌梗死组(1、3、7 d)和蜕皮甾酮干预治疗组(每只0,40mg/d).免疫组化检测VEGF表达;Ⅷ因子相关抗原标记内皮细胞,检测毛细血管密度,比重法测定梗死面积.原代培养大鼠心肌细胞,在常氧与缺氧状态下实验组分别给于蜕皮甾酮治疗(100μg/ml),24h后采用免疫细胞化学法检测心肌细胞中VEGF表达.结果随缺血缺氧时间的延长心肌产生的VEGF增加,与对照组比较各组均有显著差异,缺血时间与VEGF产生量呈正相关;蜕皮甾酮治疗组与对照组相比,血清肌酸激酶同功酶(CK-MB)显著降低(P＜0.01);毛细血管密度增加(P＜0.01);心肌梗死面积减少(P＜0.01).在常氧与缺氧状态下,蜕皮甾酮治疗组心肌细胞VEGF表达显著高于对照组(P＜0.01).结论在心肌梗死急性期缺血心肌通过分泌VEGF对自身产生重要的保护作用;蜕皮甾酮进一步刺激心肌分泌产生VEGF,促进大鼠缺血区血管生成、侧支循环建立、毛细血管密度增加,发挥心肌保护作用.     

Diabetic retinopathy is associated with a switch in splicing from anti- to pro-angiogenic isoforms of vascular endothelial growth factor

Aims/hypothesis Proliferative diabetic retinopathy results from excess blood vessel growth into the vitreous fluid of the eye. Retinal angiogenesis is regulated by expression of vascular endothelial growth factor (VEGF), and many studies have shown that VEGF is critically involved in proliferative diabetic retinopathy. VEGF is alternatively spliced to form the angiogenic (VEGF_xxx) and potentially anti-angiogenic (VEGF_xxxb) family of isoforms. The VEGF_xxxb family is found in normal tissues, but down-regulated in renal and prostate cancer. Previous studies on endogenous expression of VEGF in the eye have not distinguished between the two families of isoforms.Methods We measured VEGF_xxxb isoform expression in normal human eye tissue (lens, sclera, retina and iris) and vitreous fluid using enzyme-linked immunosorbent assay and Western blotting with a VEGF_xxxb-specific antibody.Results VEGF_xxxb protein was expressed in lens, sclera, retina, iris and vitreous fluid. Multiple isoforms were seen, including VEGF₁₆₅b, VEGF₁₂₁b, VEGF₁₄₅b, VEGF₁₈₃b and VEGF₁₈₉b. In non-diabetic patients, 64±7% of the VEGF in the vitreous was VEGF_xxxb (n=18), whereas in diabetic patients only 12.5±3.6% of total VEGF was VEGF_xxxb.Conclusions/interpretation Since VEGF_xxxb inhibits VEGF_xxx-induced angiogenesis in a one-to-one stoichiometric manner, these results show that in the eye of diabetic patients VEGF splicing was switched from an anti-angiogenic to a pro-angiogenic environment. This occurred through changes to the ratio of VEGF_xxx : VEGF_xxxb. Alterations to splicing, and through that to the balance of VEGF isoforms, could therefore be a potential therapeutic strategy for diabetic retinopathy.Konopatskaya and Perrin are joint first authors.     

A Three-dimensional Analysis of Blood Vessels in Bronchioloalveolar Carcinoma

The three-dimensional architecture of blood vessels within lung adenocarcinomas has not been well studied. In 19 cases with bronchioloalveolar carcinoma with central fibrosis, we three-dimensionally examined blood vessel architecture in 150 m thick sections stained with elastin staining and anti-CD34 antibody. We examined four regions: normal alveoli and three regions within the tumor including an area adjacent to the normal alveoli (external area), an area in which tumor cells were replacing epithelial cells (replacement area), and a central fibrotic area (fibrotic area). Elastin staining showed that elastic fibers formed the framework of the alveoli, and the alveolar structure shrank more strongly to the center of the tumor due to folding of alveolar walls invaded by adenocarcinoma cells. We also measured three vessel parameters in these four regions. The vessel diameters were 4.08±1.10 m, 3.95±1.02 m, 5.04±1.56 m, and 6.11±2.23 m, the circumferences of those vessels seen as complete circles were 43.11±12.78 m, 43.71±12.87 m, 95.21±39.32 m, and 126.77±54.65 m; the lengths between vessel bifurcations were 13.28±3.08 m, 13.47±4.58 m, 24.91±9.66 m, and 41.82±28.08 m in the normal alveoli, and the external, replacement, and fibrotic areas, respectively. Blood vessel architecture changed such that the vessels became larger and coarser towards the center of the tumor. Our three-dimensional analysis suggests continuous remodeling of alveolar capillaries rather than angiogenesis within bronchioloalveolar carcinoma.