血管生成素受体作用在婴幼儿血管瘤中的探讨

  • 2019年8月2日

   关键词 血管天生素; 婴幼儿; 血管瘤 

  中图分类号 R732.2 文献标识码 A 文章编号 1674-6805(2013)22-0149-03 

  血管发展具有两种最主的体式格局即血管发生(vasculogenesis)和血管新生(angiogenesis)1-2。血管发生是指来自中胚层的血管干细胞或内皮前体细胞经过分解、猬集和重复重塑构成
成熟血管网的进程。血管新生是指从己具有的血管上以抽芽或嵌入的体式格局构成
新的毛细血管的进程3。血管发展的整个进程中均需血管内皮细胞发展因子(vascular endothelial gowth factor,VEGF)及其受体家族的介入,而血管新生的后期尤其是血管的构建、成熟与不变需血管天生素Angiopoietin/Tie2(简称Ang/Tie2)家族的介入4。胎儿的血管发展同时具有上述两种体式格局,而成人体内生理性的血管发展只有血管新生体式格局,而无血管发生体式格局5。SALIMATH等6认为,某些幼稚的原始血管内皮细胞在妊娠晚期发生变异,增殖能力适度增强,协同细胞发展因子的作用,内皮细胞适度增殖,构成
大量的毛细血管,毛细血管重复交织、成网,最后构成
血管瘤。本文主对Ang/Tie布局及其在婴幼儿血管瘤方面的作用加以概括和总结。 

  1 血管天生素家族基因布局特点 

  血管天生素(angiopoietin,Ang)是一排泄性单链碱性卵白,由123个氨基酸残基组成。Ang属于胰腺核糖核酸酶超家族的一员,是该家族中独一含受体抑制剂和激动剂的促血管天生因子,也是目前已知的所有血管天生因子中独具核糖核酸酶活性的因子7-10。布局剖析发觉,Ang卵白晶体由三个布局域组成C-端纤维卵白原样布局域、N-端螺旋-螺旋布局域和疏水性排泄信号肽。C-端纤维卵白原样布局域包括
Ang受体结合区,决定某种Ang亚型是激动剂或是拮抗剂,该布局域是Ang家族中最保守的序列。N-端螺旋-螺旋布局域的氨基酸序列与肌球卵白及其相关卵白有较大的同源性,该布局域与血管天生素的二聚化/多聚化有关。迄今为止发觉的Ang家族具有四种体式格局,即Ang1、Ang2、Ang3和Ang4。这四种Ang都可与内皮细胞特异性的酪氨酸激酶受体Tie2结合。其中Ang1和Ang4能够引诱
Tie2的磷酸化,从而激活Tie2;而Ang2和Ang3则抑制Tie2的磷酸化,从而抑制Tie2的激活11-15。Angl基因定位于染色体8q22.3q23部位,编码498个氨基酸,分子量约为70 kD16-20。C-端纤维卵白原样布局域约莫由200个氨基酸组成,N-端螺旋-螺旋布局域约莫由180个氨基酸组成,两者之间的连接肽是 

  Ang1与细胞外基质连接的布局域21。Ang1可构成
四种同分异构体,分别编码498、367、255、154个氨基酸,分子量分别为 

  1.5 kD、1.3 kD、0.9 kD、0.7 kD 22-24。Ang2基因定位于8p23.1部位,编码496个氨基酸,分子量约为70 kD。Ang2与Ang1同源性高达60%,其N-端和C-端同样具有螺旋-布局域和纤维卵白原样布局域。Ang1的9个半胱氨酸中的8个在Ang2中是保守的,而Ang2的纤维卵白原样布局域与螺旋-螺旋布局域的交界处比Ang1少一个半胱氨酸25。Ang3基因定位于20p13部位,编码523个氨基酸,与Ang1和Ang2同源性分别为45.1%和44.7%的26。Ang4基因定位于20p13部位,编码503个氨基酸27。 

  2 血管天生素家族布局分布特点 

  Ang主表白于成人富含血管的布局器官中,在多种病理条件下如创伤、炎症、肿瘤等也可表白28。Ang1主在富含血管的布局中如胚胎期的间质细胞、成人肌肉、胎盘、前列腺、卵巢、子宫等表白。Ang2主在血管重塑生动的部位如胚胎期的大血管平滑肌、胎肝血管壁,成人卵巢、子宫、胎盘等表白29,其表白受多种因子如肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、VEGF、EGF等调节,缺氧可以增进Ang2的表白,而Ang1和TGF-β则下调其表白30。Ang3表白于肺和人脐静脉内皮细胞上,VEGF可引诱
人脐静脉内皮细胞中Ang3的高表白,并下调Ang2的表白31。Ang4主表白于肺布局内,人胶质瘤中亦可见到Ang4的表白,而在其它布局细胞内表白较低32。 

  3 血管天生素受体的布局 

  Tie是血管内皮细胞特异性的酪氨酸激酶(receptor tyrosine kinase,RTK)受体家族成员,包括Tie1和Tie2两个亚型。Tie1来源于K562细胞株,主发挥毛细血管间的液体交换和血管对血流动力学的应答等作用,并与内皮细胞的分解和布局完整性有关。目前还没有发觉Tie1的配体,故大多数研讨主集中在Tie2上33-34。Tie2为Ang的受体,布局与Tie1类似
。其基因定位于9p21部位,编码1124个氨基酸组成的卵白质。在胚胎时期,Tie2平均表白于血管内皮上,Tie2的细胞内含有1个酪氨酸激酶布局域,该布局域含有1个激酶插入布局域,细胞外由8个功能区组成,邻近
细胞膜部分为由3个连续的重复序列组成的纤维卵白,3个表皮发展因子基序分隔2个免疫球卵白样布局域。Tie2的折叠布局与丝氨酸/苏氨酸和酪氨酸激酶布局类似
,其催化核心在其羧基末端,羟基端去磷酸化构成
激活的构象。Tie2的主在增进内皮细胞的存活以及维持血管的不变性和完整性等方面发挥重的作用,其受体后途径也许是经由进程作用于PI3、AKT等激酶,激活转录因子STAT,增进p21转录等对血管天生起调节作用35。 

  4 婴幼儿血管瘤与Ang及其受体Tie2途径 

  婴幼儿血管瘤是小儿最稀有的良性肿瘤之一,其发病率约在5%~10%36。性别和种族的差异可影响其发病率,考察显现男女发病率比例约为1∶3,高加索人的发病率高达10%。血管瘤的不凡性不但
仅是它较高的发病率,而且它可以在无任何干预医治下自行衰退。临床通常分为增殖期(0~1岁),衰退期(1~5岁),衰退完全期(5~10岁)。婴幼儿血管瘤好发于面部,最后发觉时光约在出生后2周~1个月间,随后的半年内肿瘤发展迅速,大部分血管瘤不需不凡医治,1年后便可逐步自然衰退,衰退率可达80%。但是,有部分婴幼儿血管瘤在发生发展进程中也许发生各类并发症,如出血、溃疡、感染等,严重者可危及生命。约有30%的患儿在瘤体衰退后会遗留色素沉着、皮肤萎缩、皮肤瘢痕、畸形等后遗症,给患儿带来严重的肌肤损害和心理创伤37-38。根据临床传统分类体式格局,将血管瘤分为毛细血管瘤、海绵状血管瘤、蔓状血管瘤、混合型血管瘤。血管瘤的病理学特点是血管内皮细胞的异样适度增殖和血管异样天生。目前国内外对于血管瘤中Ang及其受体Tie2家族的表白情形研讨和报导的较少。Nasser等39研讨发觉婴幼儿血管瘤布局中Ang2及其受体Tie2及bFGF、VEGF等发展因子表白均增高,而Ang1表白则与此相反。体外培养血管瘤内皮细胞和正常血管内皮细胞时发觉,血管瘤内皮细胞较正常血管内皮细胞对Ang1和VEGF细胞应答及Ang2/Tie2的表白均升高。原位杂交体式格局显现,与衰退期血管瘤比拟,增生期血管瘤的Ang2及Tie2基因的mRNA水平增高40。以上均表白Ang/Tie2体系也许在血管瘤的血管天生进程中起重作用。正常情形下,Ang1起维持血管不变的作用,因为Ang1表白降低,而Ang2表白增高,血管正常的不变状态被削弱,血管内皮细胞与外周细胞之间的相互联络也被破坏,招致血管基底膜与细胞外基质裂解,血管内皮与基质处于不不变状态,协同VEGF等发展因子的作用,内皮细胞迁徙、增殖生动,内皮细胞大量沉积,终究
招致血管瘤的发生。故推测,失衡表白的Ang/Tie2体系,自身被激活,在众多发展因子的协同作用下,血管内皮细胞异样增殖并大量沉积,招致脉管零碎构成
错乱,终究
引诱
婴幼儿血管瘤的构成
。Wang等41报导显现人类肌间血管瘤上发觉内皮细胞有渐变的Tie2过表白,而且该内皮细胞增殖增加。Boye等42研讨发觉原代和传代的血管瘤内皮细胞较人类皮肤毛细血管内皮细胞增殖率和迁徙率均增高。以上研讨了局均表白内皮细胞自身出现异样是血管瘤发生的根本原因。因为基因渐变,Ang/Tie2通路被激活,招致内皮细胞增殖错乱,终究
引诱
血管瘤构成
。但具体的渐变基因及渐变位点目前还还没有被证实。

  综上所述,血管瘤医治体式格局单一,目前国内、外仍没有一种药物或医治手段能根治各类型的血管瘤,多数药物的机制尚不明确。怎样在医治中做到医治确切、副作用小是目前急需解决的一大难题,还有待于医学工作者的不断探索。选择效果更好,副作用更小的药物将会是当前医治研讨的方向。分子医治、基因医治是医学医治的新的方向。婴幼儿血管瘤的病理生理学机制与Ang及其受体Tie2零碎密切相关。目前血管瘤的医治都具有一定的局限性,随着基因及卵白组学的进步,也许经由进程基因调控和特异性抗体对Ang及其受体的作用,为肿瘤患者的医治提供了新希望和新的突破。 

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