2. 中国热带农业科学院热带作物品种资源研究所, 海口 571101
2. Tropical Crop Germplasm Research Institute, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China
妊娠期间,母猪由于无法提供足够的营养物质以满足各个子宫角上全部胎猪的正常生长发育需要,所以猪是宫内发育迟缓(intrauterine growth retardation,IUGR)表现最严重的多胎高产家畜动物[1-2]。IUGR不仅影响新生仔猪初生重,而且对其后代的生长发育也会产生众多负面影响[1]。引起IUGR发生的原因包括遗传、子宫内环境和胎盘等因素,其中胎盘功能障碍或形态异常是引起IUGR发生的主要因素之一[1, 3]。在宫内发育过程中,母体中的养分依靠血液到达子宫内膜,并通过胎盘汇集到脐带输送给胎儿。一般而言,根据母体的供给能力、胎儿的需求,以及胎盘分泌的激素和生长因子,共同调节胎盘将营养物质向胎儿运输。胎盘运输营养物质的能力取决于胎盘的大小、交换表面积、血管密度以及血流量[4]。研究表明,IUGR仔猪的胎盘血管生成能力要显著低于正常初生重仔猪的胎盘,提示胎盘血管发育异常会损害胎儿氧气和营养物质的正常供应,从而导致IUGR仔猪的发生[5]。因此,本文结合国内外最新研究进展对胎盘血管发育及其在IUGR仔猪发生中的作用进行综述,旨在为降低IUGR仔猪的发生提供参考。
1 胎盘的功能及发育胎盘是母体妊娠期特有的一个临时性器官,将母体与胎儿紧密连接在一起。母体通过胎盘为胎儿提供氧气、葡萄糖、氨基酸和脂肪酸等营养物质,胎儿也将代谢废物通过胎盘排出[3]。猪胎盘属于弥散型上皮绒毛膜胎盘,具有胎儿面和母体面2个血液循环系统,二者之间相互独立且不发生直接接触[6]。猪胚胎在植入过程中不会侵入子宫壁,而是附着在子宫腔上皮上[7]。妊娠第13天,子宫黏膜上皮细胞初次与胎儿滋养层细胞接触将母体与胎儿联系在一起,形成绒毛膜上皮/子宫内膜上皮双细胞层结构[7-8]。此阶段胎盘生长迅速,需要大量的营养物质供给,用于随后血管生成和子宫内膜的形成,为妊娠后期胎儿的快速生长做好准备。在妊娠第30~35天,双细胞层开始形成褶皱[9]。之后随着妊娠的进一步推进,母体胎盘和胎儿胎盘组成的子宫-胎盘界面经历了相当大的形态变化,绒毛膜逐渐嵌入子宫内膜皱褶凹陷处以缩短两者之间距离,达到使双细胞层嵌合更加紧密的目的,褶皱变的多且复杂[10]。到妊娠后期,双细胞层进一步发育,绒毛膜和子宫内膜接触面积达到最大,两者距离达到最近,使胎儿和母体血液之间的距离降低,以确保营养物质的正常供给。
2 胎盘血管的发育猪胎盘血管发生在妊娠初期,包括血管形成(vasculogenesis)和血管新生(angiogenesis)2个过程。早期人胎盘中的血管形成,即形成新的血管,由多能间充质细胞分化成造血干细胞形成早期的血管网[11]。造血干细胞是形成毛细血管的原始细胞,可进一步分化成血管内皮祖细胞和血管母细胞,随后血管内皮祖细胞和血管母细胞在生长因子作用下诱导血管形成向血管新生转变,细胞相连形成最初的毛细血管管腔[12]。血管新生,定义为通过内皮细胞的迁移和增殖,从现有的毛细血管中以分支(通过发芽形成新血管)和非分支(通过伸长形成毛细血管环)的方式形成新的血管[12]。血管新生主要包括血管伸长、嵌入、出芽、血管套叠4种方式[13],妊娠早期血管以分支状生长(包括出芽和血管套叠)为主,中晚期妊娠期间以非分支状生长血管(包括血管伸长和嵌入)为主[14]。在早期胎盘形成期间,血管新生在组织生长和修复中起着不可或缺的作用,是确保胎盘发育正常的必要环节。
猪胎盘血管在植入后迅速形成,第19天尿囊血管进入绒毛膜,第25天在胎盘和尿囊膜中清晰可见血管,第30天绒毛膜被尿囊血管广泛地血管化[3]。胎盘在妊娠晚期发育成高度血管化的器官,与胎儿相邻的中央区可称为高血管胎盘,而两侧剩余的附着胎盘是低血管胎盘,胎盘和未附着胎盘之间的子宫区域将被称为坏死尖端,在妊娠第22~42天,胎盘由这3个部分组成[15]。Cristofolini等[16]对母猪妊娠过程中胎盘血管进行了形态测量,发现在妊娠早期(第25、30和40天)和妊娠中期(第60和70天),面积为100~500 μm2的血管较多,而在妊娠晚期则发现大量面积为1~100 μm2的血管。
3 胎盘血管发育在IUGR发生中的作用仔猪的出生体重与胎盘血管密度呈正相关,IUGR仔猪胎盘结构异常已经得到研究的证实,主要表现在血管密度降低、绒毛数量、直径和表面积的减少,以及动脉数量、管腔大小和分支的减少[17]。这些异常都会影响胎盘功能,降低胎儿发育所需要的营养物质。在IUGR胎儿的胎盘中,也发现滋养细胞侵袭和母体子宫血管向螺旋动脉的生理重塑不足[18]。螺旋动脉重塑是指滋养层细胞沿着动脉壁向上游移动,破坏平滑肌细胞并取代它们[19]。重塑主要有2个影响:一是降低了母体血液流入胎盘绒毛间隙的速度和脉动性;二是平滑肌的丧失使自发血管收缩的风险降低[20]。通过对子宫螺旋动脉重塑,使之重新成为高流量、低阻力的血管,继续为妊娠期胎儿提供充足的氧气和营养物质。因此,妊娠期母猪胎盘血管的正常发育对于胎猪的生长发育起至关重要的作用。
4 调控胎盘血管发育的分子机制 4.1 血管内皮生长因子(vascular endothelial growth factor,VEGF)信号通路VEGF对胎儿和胎盘界面的血管生成至关重要,VEGF信号通路也是控制妊娠期间局部血流量的关键通路。VEGF通过与血管内皮细胞生长因子受体1/2(vascular endothelial growth factor receptor 1/2,VEGFR1/2)结合,激活下游信号通路,从而发挥其促血管生成的作用。敲除VEGF和VEGFR1/2基因可引起胎盘血管生成受损和胚胎死亡率增高[21-22],说明VEGF信号通路在胎盘血管生成中起着重要作用。与其他物种一样,VEGF及其受体在猪胎盘组织中大量表达,效率高的胎盘在妊娠第90天时具有较高表达的VEGF[23],低出生体重仔猪胎盘中可观察到血管生成减少和VEGF-A蛋白表达量降低的现象[24]。鉴于VEGF在血管生成中扮演的重要角色,推测VEGF表达量降低是导致IUGR仔猪胎盘血管生成异常的原因,但其中的分子机制还有待进一步研究。
4.2 丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号通路MAPK信号通路主要包括细胞外信号调节激酶1/2(extracellular regulated protein kinases,ERK1/2)通路、c-Jun氨基末端激酶(c-Jun N terminal kinases,JNK)通路、p38丝裂原激活蛋白激酶(p38 mitogen-activated protein kinases,p38)通路[25]。与VEGF功能相似,成纤维细胞生长因子2(fibroblast growth factor 2,FGF2)是调节胎盘血管生长和血管重塑的因子。在胎盘血管内皮细胞中,MAPK的激活在VEGF和FGF2刺激的血管内皮细胞增殖、迁移和血管形成中是不可或缺的[14]。除此之外,抑制ERK1/2和JNK1/2通路完全阻断了VEGF介导的细胞增殖以及迁移[26],激活JNK通路还可诱导VEGF表达[27]。因此,激活ERK和JNK通路可使细胞中VEGF表达增加,进而促进细胞增殖和迁移。此外,胎盘血管生成也需要p38的参与,FGF2通过激活p38诱导蛋白激酶B(protein kinase B,AKT)磷酸化促进血管的形成和迁移[28],而敲除p38 α基因会引起胎盘迷路层血管缺乏以及凋亡率增加,导致胎盘血管生成受阻[29]。
4.3 磷脂酰肌醇3激酶(phosphatidylinositol 3 kinase,PI3K)/AKT信号通路PI3K/AKT信号通路是血管生成的重要调节器,抑制PI3K/AKT会导致一氧化氮(NO)产生受到抑制,并完全阻断VEGF介导的细胞增殖和迁移作用[26, 30]。AKT是PI3K的一个下游靶蛋白,AKT1缺失的小鼠胎盘表现出明显的血管化降低现象,且胎儿体重和存活率均下降[31]。AKT的激活对于VEGF刺激内皮细胞迁移是必要的[32],提示AKT1表达异常可能是引起IUGR胎儿胎盘血管生成异常的重要原因,其中的机制可能与VEGF有关。
4.4 内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)-NO信号通路NO是由eNOS、诱导型一氧化氮合酶(iNOS)和神经元一氧化氮合酶(nNOS)催化生成。在eNOS缺失的妊娠小鼠中,子宫胎盘血流量减少、子宫动脉直径和螺旋动脉长度减少,连接区胎盘缺氧的标记物升高[33]。eNOS衍生的NO可增加小鼠胎盘血流量、胎盘血管生成和胎儿生长,维持较低的胎盘血管阻力[34],而在eNOS缺乏的小鼠中,VEGF不能诱导新的血管形成[35]。但有研究表明,eNOS在IUGR胎盘中高表达[36],这可能是由于eNOS活性提高是一种补偿机制,以改善血流和加强对IUGR胎儿的营养支持,维持胎儿的正常发育。
4.5 信号传导与转录激活因子3(signal transducer and activator of transcription 3,STAT3)信号通路STAT3是调控VEGF-A的转录因子,其活性增强可促进细胞增殖、迁移和血管生成[37]。最新研究表明,还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶2(NADPH oxidases 2,Nox2)是调控STAT3的重要因子,Nox2诱导产生的线粒体活性氧(ROS)可抑制STAT3磷酸化降低VEGF-A的表达,从而降低胎盘血管生成[38]。相同的研究也表明,调节Nox2-ROS信号通路可影响猪血管内皮细胞VEGF-A的表达,从而影响细胞增殖、迁移和管形成[39]。可见STAT3发挥促血管生成的作用主要是通过调控VEGF表达来实现的。
5 调控胎盘血管发育的营养因素 5.1 葡萄糖葡萄糖是胎儿和胎盘主要的能量来源,除了用于维持母体和胎儿的正常需要外,还可激活PI3K/AKT信号通路促进滋养层细胞中VEGF的表达,从而促进胎盘血管生成[40]。抑制葡萄糖的吸收,则可以降低细胞的生长和血管生成。许多患有IUGR的胎儿(羊)患有低血糖症,这是由于胰岛素分泌和葡萄糖摄取不足[41]。而在妊娠期间需根据母体的实际情况,适量给予母体葡萄糖的供应。高血糖为特征的疾病影响胎盘正常发育,表现出异常的胎盘环境和异常的胎盘血管生成[42],这主要是由于高血糖引起胰岛素分泌和缺氧调节血管生成因子表达异常。高浓度葡萄糖导致胎盘血管阻力增加,降低内皮细胞的血管生成能力,损害胎盘血管的正常发育[43-44]。在肥胖母猪中发现母体葡萄糖浓度上升和胎盘血管生成降低的现象[45],这可能是由于葡萄糖浓度上升降低了胎盘VEGF表达量,从而引起胎盘血管生成受损。
5.2 多胺多胺(腐胺、亚精胺和精胺)在调节胎盘基因表达、信号转导、DNA和蛋白质合成以及细胞增殖和分化中起着至关重要的作用[46]。胎盘多胺合成率在羊妊娠早期,即胎盘快速生长期间达到最大[47]。多胺具有调节血管生成、早期胚胎发生、胎盘滋养细胞生长和胚胎发育的作用[48]。比如在猪滋养外胚层细胞中添加腐胺可增加磷酸化哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)及其下游靶标真核细胞翻译起始因子4E结合蛋白1(eukaryotic translation initiation factor 4E binding protein 1,4EBP1)和p70 S6蛋白激酶1(p70 S6 protein kinase 1,p70 S6K1)蛋白的丰度,从而促进细胞增殖[49]。在哺乳动物中,多胺有3个来源:1)氨基酸合成,例如精氨酸、脯氨酸、甲硫氨酸和鸟氨酸;2)饲粮;3)由肠道微生物群产生[50]。
5.3 氨基酸精氨酸是多胺和NO合成的前体,NO作为血管扩张和血管生成因子,能够穿过细胞膜,与血管平滑肌细胞上面的受体结合,对胎盘血管生成和血流起作用[51]。精氨酸的补充会增强内皮细胞NO的合成,致使胎盘的血流量增加,从而母体到胎儿的营养和氧气供应增加。在妊娠第14~25天,饲粮添加0.4%或0.8%的L-精氨酸可提高猪的胎儿存活率,同时胎盘血管数量增加18.5%,胎盘血管的直径增加18.2%[52]。在妊娠后期饲粮中添加0.4%精氨酸和0.6%谷氨酰胺可促进胎盘血管生长,提高胎儿的存活率和生长速度,并减少活产仔猪出生体重的变化,降低IUGR的发生率[53]。精氨酸和谷氨酰胺这2种氨基酸作为组织蛋白的构建基质以及多胺和NO产生的底物,可通过促进DNA和蛋白质合成促进胎盘中的血管生成[3]。由此看出,可以通过添加精氨酸和谷氨酰胺来改善胎盘血管生成,从而减少IUGR的发生率。脯氨酸是猪胎盘中多胺合成的主要氨基酸,在妊娠早期合成最高,具有促进胎盘生长和血管生成的作用[54]。研究发现,IUGR胎猪尿囊液和羊水中的脯氨酸浓度远低于正常窝产猪[55]。蛋氨酸也可促进胎盘组织中VEGF-A的表达,当高产母猪妊娠饲粮中蛋氨酸与赖氨酸的比例为0.37时,仔猪的出生体重和胎盘血管生成增加[56]。此外,IUGR大鼠从妊娠中期开始补充瓜氨酸后,胎儿体重、胎盘效率、血管生成相关基因VEGF和VEGFR1的表达出现提高[57]。以上研究结果表明,在饲粮中添加特定的氨基酸是一种有效促进胎盘血管生成和达到胎儿发育的手段,但由于氨基酸的作用效果受到母体品种、生理状态、饲粮自身氨基酸含量、环境等众多因素的影响,使得氨基酸促血管生成的效果并不稳定,未来的研究还需要综合母体品种、生理状态等因素来评估氨基酸调控胎盘血管生成的作用。
5.4 脂肪酸在子宫内,胎盘从母体中选择性摄取二十二碳六烯酸(DHA)和花生四烯酸(ARA)以丰富胎儿的血液循环。研究发现,ARA可通过产生类花生酸刺激血管生成,DHA通过刺激VEGF的表达来刺激胎盘早期妊娠滋养层细胞的管形成,并增加毛细血管长度和绒毛外滋养层细胞的管数量[58]。此外,二十碳五烯酸(EPA)、DHA和ARA通过刺激血管生成素4(angiopoietins 4,ANGPTL4)的表达,调节胎盘绒毛滋养层细胞中的血管生成[59]。共轭亚油酸可通过提高ANGPTL4的表达,并通过增加DHA在这些细胞中的摄取来调节早期胎盘的血管生成过程[60]。脂肪酸除了刺激主要血管生成因子如VEGF和ANGPTL4的表达外,还可诱导细胞内脂肪酸结合蛋白家族(fatty acid binding proteins,FABPs)中FABP4和FABP3的表达[61]。FABP4是VEGF/VEGFR2信号通路的新靶点,也是内皮细胞细胞增殖和血管生成的积极调节因子,参与VEGF介导的血管生成[61-62]。FABP4通过促进内皮细胞增殖和迁移发挥促血管生成作用[63]。因此,脂肪酸除了诱导血管生成因子生成外,也可直接或间接调节血管生成过程。
5.5 维生素α-生育酚(alpha-tocopherol,αT)是哺乳动物组织中的主要生育酚,在胎盘发育过程中必不可少,敲除妊娠小鼠αT转移蛋白,会导致胎盘发育严重受损,迷路滋养层细胞明显减少[64]。在妊娠后期,怀孕母羊饲喂αT通过提高VEGF表达促进胎盘的血管生成[65]。在这个过程中,αT通过磷酸化为α-生育酚磷酸酯,刺激VEGF的产生,导致血管生成的增加[66]。因此,补充αT可促进血管生成以增加对胎儿的营养供应。维生素D在妊娠期间起着关键作用,其缺乏降低胎盘VEGF和VEGFR1的蛋白表达水平,引起IUGR发生,并对出生后后代健康产生不良后果[67]。而补充维生素D可使胎盘VEGF和VEGFR1的蛋白水平正常化,促进胎盘血管生成[68],体外研究[69]也同样证实了上述结果。胎盘发育过程中的血管生成和滋养层侵袭需要叶酸的参与,母体接触叶酸拮抗剂会导致严重的胎盘早剥和IUGR,而补充叶酸和DHA可刺激胎盘滋养层细胞的增殖[70-71]。以上研究结果表明,通过调控母体维生素摄入水平,可促进胎盘血管生成,保证胎盘的正常发育。
5.6 其他功能性活性物质安石榴苷具有抗氧化和抗炎等功能,妊娠高血压大鼠补充安石榴苷,可观察到胎盘中氧化应激标志物减少,VEGF和NO表达水平提高[72]。这一研究结果表明补充安石榴苷可降低妊娠大鼠氧化应激,并恢复血管生成平衡。半胱胺是一种抗氧化保护剂,妊娠母猪饲粮中添加可以减轻氧化应激,提高母猪的繁殖性能,并提高胎盘血管密度和VEGF-A的mRNA水平[39]。体外研究发现,添加姜黄素可促进细胞生长、迁移和血管生成[73]。此外,在胎盘功能不全小鼠母体中补充胆碱,也可增加胎盘血管生成,减少炎症和胎盘凋亡[74]。然而目前功能性活性物质对猪胎盘血管生成的研究报道还较少,未来的研究可以探讨植物提取物对猪胎盘血管生成的作用,筛选出更多具有促进猪胎盘血管生成的功能活性物质。
6 小结与展望胎盘血管生成异常是引起IUGR仔猪发生的一个重要因素,但由于胎盘血管生成是一个受母猪品种、环境、营养和管理等因素影响的高度复杂的生理过程,对于IUGR仔猪胎盘血管生成异常缺乏足够的认识,这限制了精准营养策略的提出。未来的研究可以利用组学和分子生物学等技术,筛选和鉴定调控猪胎盘血管生成的基因,并揭示其潜在的分子机制,不仅有利于提高人们对于IUGR仔猪发生的认识,而且还可为精准营养调控提供新的调控靶点。
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