血管内皮生长因子促进绵羊卵母细胞体外成熟机理研究
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摘要
本研究通过10个系列试验,在绵羊卵母细胞体外培养液中添加血管内皮生长因子(Vascular Endothelial Growth Factor,VEGF),研究VEGF对绵羊卵母细胞体外受精及胚胎发育的影响,并通过绵羊卵母细胞成熟过程中细胞的形态学结构、细胞骨架、胞内丝裂原活化蛋白激酶(P44/p42 Mitogen-activated Protein Kinases,P44/p42 MAP kinases)、蛋白激酶C (Protein Kinase C,PKC)和酪氨酸蛋白激酶(Protein Tyrosine Kinases,PTK)活性的变化,以及VEGF及其两受体KDR/Flk-1和Flt-1在绵羊卵母细胞成熟过程中表达的研究,揭示VEGF对绵羊卵母细胞体外成熟的作用和机理。
一、血管内皮生长因子对绵羊卵母细胞体外成熟、体外受精及胚胎发育的影响
试验1:不同浓度VEGF对绵羊胚胎体外发育的影响
在绵羊卵母细胞体外成熟培养液(TCM199+胎牛血清)、HSOF受精液及SOF胚胎发育液中添加不同剂量的VEGF(对照组0 ng/ml、试验组Ⅰ5 ng/ml和试验组Ⅱ10 ng/ml),研究其对卵母细胞成熟和早期胚胎发育的影响。结果显示:对照组、试验组Ⅰ、试验组Ⅱ卵母细胞成熟率分别是80.68%、86.09%和85.22%。试验组Ⅰ和试验组Ⅱ与对照组相比,极显著的提高了卵母细胞成熟率(P<0.01),但试验组Ⅰ和试验组Ⅱ之间差异不显著。试验组Ⅰ和试验组Ⅱ的卵裂率分别是75.18%和73.48%,高于对照组的69.38%,但差异不显著。试验组Ⅰ的桑葚胚率和囊胚率是45.45%和30.06%,极显著的高于对照组37.61%和23.65%(P<0.01);同时试验组Ⅱ的桑葚胚率和囊胚率是40.25%和27.80%,低于试验组Ⅰ,高于对照组,但差异不显著。结果表明:体外培养液中添加5ng/mlVEGF为适宜添加量,VEGF明显提高了受精卵发育到桑葚胚和囊胚的能力。
试验2:BSA成熟培养液中添加VEGF对绵羊卵母细胞体外成熟、体外受精及胚胎发育的影响
本试验采用在成分相对明确的BSA成熟培养液系统中,添加不同浓度VEGF,检测对卵母细胞成熟和胚胎发育的作用。成熟培养液(TCM199+BSA)中分别添加0 ng/mlVEGF对照组、5 ng/ml、10 ng/ml的VEGF试验组卵母细胞成熟培养后,经体外受精和体外培养。结果显示:试验组Ⅰ和试验组Ⅱ的成熟率分别是83.98%和80.23%,对照组是75.76%。试验组Ⅰ和试验组Ⅱ与对照组相比,极显著的提高了绵羊卵母细胞的成熟率(P<0.01),并且试验组Ⅰ和试验组Ⅱ之间差异显著(P<0.05)。试验组Ⅰ的卵裂率是79.39%,高于试验组Ⅱ和对照组的72.24%和75.85%,差异不显著。试验组Ⅰ桑葚胚率是45.03%,明显高于试验组Ⅱ和对照组38.85%和38.94%的桑葚胚率,差异不显著。试验组Ⅰ囊胚率是23.54%,极显著高于对照组的18.09%(P<0.01);试验组Ⅱ囊胚率是21.05%,高于对照组Ⅰ的18.09%,差异不显著。结果表明:BSA成熟培养液中添加5ng/ml VEGF为适宜添加量,对绵羊卵母细胞体外胚胎的发育有积极的促进作用。
试验3:VEGF添加对绵羊卵母细胞体外受精多精入卵的影响
在绵羊卵母细胞体外成熟培养液(TCM199+BSA)中添加不同剂量的VEGF(对照组0 ng/ml和试验组5 ng/ml)成熟培养,经体外受精培养后,地衣红染色结果显示:试验组和对照组的受精率分别是83.86%和75.75%,多精入卵率分别是7.68%和12.64%,未受精率是8.47%和11.60%。试验组受精率极显著高于对照组(P<0.01);试验组多精入卵率极显著低于对照组(P<0.01);试验组的未受精率显著低于对照组(P<0.05)。结果表明:VEGF明显降低了多精入卵率,有效的抑制了绵羊卵母细胞受精过程中的多精入卵现象的发生。
二、VEGF促进绵羊卵母细胞体外成熟的机理研究
1、VEGF对绵羊卵母细胞体外成熟过程中细胞核成熟和细胞质成熟的影响
试验4:在绵羊卵母细胞体外成熟培养液(TCM199+BSA)中添加不同剂量的VEGF(对照组0 ng/ml和试验组5 ng/ml)进行成熟培养,再采用地衣红染色技术,研究VEGF对绵羊卵母细胞体外成熟过程中染色体形态的影响。结果显示:试验组拥有正常染色体成熟卵母细胞的成熟率是87.42%,高于对照组的83.89%。结果表明:VEGF对卵母细胞体外成熟和维持染色体正常形态具有一定的促进作用。
试验5:在BSA成熟培养系统中成熟培养后,采用免疫细胞化学和激光共聚焦显微技术,研究VEGF对绵羊卵母细胞体外成熟过程中α-tubulin蛋白和微管组织中心(Microtubule Organizing Centers,MTOCs)时空迁移和重新组装的影响。结果显示:试验组与对照组相比,极大的促进了α-tubulin从微管组织中心向染色体的空间迁移和重新组装。同时试验得出,试验组和对照组的微管蛋白和MII期染色体的正常分布率分别是77.50%和62.60%。试验组与对照组相比,极显著的提高了微管蛋白和MII期染色体的正常分布率(P<0.01)。结果表明:VEGF促进了MTOCs从胞内和皮质区的消失,并加速了α-tubulin重新分配和向染色体的聚集,有效的提高了卵母细胞核成熟质量。
试验6:在BSA成熟培养系统中成熟培养后,采用免疫细胞化学和激光共聚焦显微技术,研究VEGF对绵羊卵母细胞体外成熟过程中皮质颗粒(Cortical Granule,CGs)时空迁移和重新组装的影响。结果显示:试验组与对照组相比,极大的促进了CGs从胞质向皮质区的时空迁移。试验组和对照组的皮质颗粒正常迁移分布率分别为79.24%和60.97%。试验组与对照组相比,极显著的提高了皮质颗粒正常迁移分布率(P<0.01)。结果表明:VEGF通过促进绵羊卵母细胞成熟过程中CGs的时空迁移,对绵羊卵母细胞胞质成熟具有积极促进作用。
2、VEGF对绵羊卵母细胞体外成熟过程中细胞超微结构变化的影响
试验7:在绵羊卵母细胞体外成熟培养液(TCM199+BSA)中添加不同剂量的VEGF(对照组0 ng/ml和试验组5 ng/ml)进行成熟培养,再结合透射电镜技术,研究VEGF对绵羊卵母细胞体外成熟过程中细胞超微结构变化的影响。结果显示:①VEGF有效促进了微绒毛的发育和变化,增加了游离端斜行插入透明带微绒毛的数量,促进了细胞内外物质交流和养分的吸收;②VEGF促进了皮质颗粒在卵母细胞成熟培养过程中向皮质区迁移的时间和空间变化;③发现特征性绵羊卵母细胞线粒体――带帽状线粒体,并且VEGF对线粒体的迁移有一定的促进作用;④VEGF的添加对卵母细胞成熟过程中脂滴数量的增加没有显著的作用,但VEGF减少了小脂滴聚集为大脂滴。
3、VEGF对绵羊卵母细胞体外成熟过程中胞内磷酸化P44/p42 MAP kinases、PKC和PTK活性变化的影响
试验8:在绵羊卵母细胞体外成熟培养液(TCM199+BSA)中添加不同剂量的VEGF(对照组0 ng/ml和试验组5 ng/ml)进行成熟培养,再结合酶联免疫技术,检测胞内磷酸化P44/p42 MAP kinases、PKC和PTK活性的变化。结果显示:绵羊卵母细胞成熟过程中三种磷酸化激酶活性都呈波动变化,试验组的P44/p42 MAP kinases、PKC和PTK相对含量始终高于对照组相对含量。成熟培养16小时和20小时时,试验组P44/p42 MAP kinases(Erk1和Erk2)含量显著高于对照组(P<0.05);成熟培养16、21小时和24小时时,试验组PTK含量显著升高于对照组(P<0.05)。结果表明:VEGF添加到绵羊卵母细胞成熟培养液中,改变了PTK磷酸化水平,进一步引起信号传递分子MAP kinase和PKC的磷酸化,从而有效促进了绵羊卵母细胞体外成熟。
4、VEGF及其受体KDR/Flk-1和Flt-1在绵羊卵母细胞体外成熟过程中的表达
试验9:在绵羊卵母细胞体外成熟培养液(TCM199+BSA)中添加不同剂量的VEGF(对照组0 ng/ml和试验组5 ng/ml)进行成熟培养,再结合RT-PCR技术,研究VEGF及其受体KDR/Flk-1和Flt-1mRNA在绵羊卵母细胞体外成熟过程中颗粒细胞和卵母细胞细胞中的表达。结果显示:①卵母细胞培养前VEGF mRNA在卵母细胞中就有表达。在整个成熟过程中对照组中其表达一直持续,但比培养前的表达量有所下降;在试验组中,VEGF mRNA在卵母细胞中的表达呈下降趋势,到成熟培养24小时时表达量微弱;卵母细胞培养前VEGF mRNA在颗粒细胞中有表达。到培养8小时时,对照组表达量升高,但后期表达量明显下降。试验组在培养8小时时表达量就已经下降,24小时时持续低水平表达。②卵母细胞培养前Flt-1 mRNA在卵母细胞中有微弱表达,随着培养时间的延续表达量明显下降。培养8小时和24小时对照组比试验组表达强,到24小时试验组几乎检测不到Flt-1 mRNA的表达;卵母细胞培养前Flt-1 mRNA在颗粒细胞中有表达,到8小时时对照组表达加强,随培养时间延续其表达量下降,直至24小时检测不到。试验组从培养8小时开始就几乎检测不到Flt-1 mRNA的表达。③卵母细胞培养前KDR/Flk-1 mRNA在卵母细胞中有微弱表达,随着培养时间的延续,无论是试验组还是对照组其表达量都明显上升;卵母细胞培养前KDR/Flk-1 mRNA在颗粒细胞中有强表达,随培养时间的延续其表达量在对照组培养8小时时加强,但在试验组中减弱,培养到24小时时,两组表达量都很微弱。结果表明:外源VEGF的加入,改变了卵母细胞和颗粒细胞中VEGF及其受体KDR/Flk-1和Flt-1 mRNA的表达。
试验10:结合免疫细胞化学和激光共聚焦显微技术,研究KDR/Flk-1和Flt-1蛋白在卵母细胞成熟观过程中颗粒细胞和卵母细胞中的表达。结果显示:绵羊卵母细胞成熟培养过程中,无论是在卵母细胞膜表面还是在颗粒细胞膜表面都检测到KDR/Flk-1和Flt-1蛋白的表达。
To investigate the effect of vascular endothelial growth factor (VEGF) on the ovine oocytes maturation and the early development of embryo in vitro, a series of ten experiments were conducted with VEGF supplemented to the maturation medium、the fertilization medium and the culture medium respectively. To show the mechanism of VEGF on promoting ovine oocyte maturation in virto by evaluate cell cycle-dependent modifications in cell configuration, cell framework, the change of active MAPK/PKC/PTK in oocyte, the expression of VEGF and its receptors KDR/Flk-1 and Flt-1 in ovine oocytes undergoing in vitro maturation.
1、The effect of VEGF on the ovine oocytes maturation and the early development of embryo in vitro
Experimentation 1: Human recombinant VEGF165 was employed at 5 ng/ml and 10 ng/ml in maturation media(TCM199+fetal bovine serum, FBS), HSOF fertilization media and SOF culture media in this study. The results showed that the maturation rate was increased significantly (p <0.01) from 80.68% in the control(0 ng/ml VEGF) to 86.09% and 85.22% in the treatment groupⅠ(5 ng/ml VEGF)and the treatment groupⅡ(10 ng/ml VEGF) respectively. The cleavage rate was increased from 69.38% in the control group to 75.18% and 73.48% (p>0.05) in the treatment groupⅠand the treatment groupⅡrespectively. The development rates of morulae and blastocyst in the treatment groupⅠ(45.45% and 30.06%) were higher significantly (p <0.01)than that of the control group (37.61% and 23.65%). And the development rates of morulae and blastocyst in the treatment groupⅡ(40.25% and 27.80%)were lower than that of the treatment groupⅠ(P>0.05) and higher than that of the control group(P>0.05). These results indicated that maturation medium, fertilization medium and the culture medium with 5 ng/ml of recombinant human VEGF165 significantly improved the maturation and fertilization of ovine oocytes and consequently the rate of embryos development were markedly enhanced. VEGF may be one of the important regular factors in system of maturation and fertilization of ovine oocyte and the early development of ovine embryo in vitro.
Experimentation 2: Human recombinant VEGF165 was employed at 5 ng/ml and 10 ng/ml in maturation media(TCM199+ bovine serum albumin, BSA), HSOF fertilization media and SOF culture media in this study. The results showed that the maturation rate was increased significantly (p <0.01) from 75.76% in the control (0 ng/ml VEGF) to 83.98% and 80.23% in the treatment groupⅠ(5 ng/ml VEGF)and the treatment groupⅡ(10 ng/ml VEGF) respectively. The cleavage rate was increased from 75.85% in the control group to 79.39%(p>0.05) in the treatment groupⅠ.The development rates of morulae and blastocyst in the treatment groupⅠ(45.03% and 23.54%) were higher significantly (p <0.01)than that of the control group (38.94% and 18.09%). And the development rates of morulae and blastocyst in the treatment groupⅡ(38.85% and 21.05%)were lower than that of the treatment groupⅠ(P>0.05) and higher than that of the control group(P>0.05). These results indicated that BSA maturation medium with 5 ng/ml of recombinant human VEGF165 significantly improved the maturation and fertilization of ovine oocytes and consequently the rate of embryos development were markedly enhanced also. VEGF may be one of the important regular factors in system of maturation and fertilization of ovine oocyte and the early development of ovine embryo in vitro.
Experimentation 3: Human recombinant VEGF165 was employed at 5 ng/ml in maturation media(TCM199+ bovine serum albumin, BSA) in this study. The results showed that the fertilization rate was increased significantly (p <0.01) from 75.75% in the control (0 ng/ml VEGF) to 83.86% in the treatment group (5 ng/ml VEGF) and the polyspermy rate was decreased significantly (p <0.01)from 12.64% in the control to 7.68% in the treatment group. The no fertilization rate was decreased (p <0.05) from 11.60% in the control to 8.47% in the treatment group. These results indicated that VEGF obviously decreased the polyspermy rate and bated the phenomenon of polyspermy in the process of ovine oocytes IVF.
1、The mechanism of VEGF on promoting ovine oocyte maturation in vitro
1.1 The effect of VEGF on the nuclear and cytoplasmic maturation of ovine oocytes matured in vitro
Experimentation 4: Human recombinant VEGF165 was employed at 5 ng/ml in maturation media (TCM199+ bovine serum albumin, BSA) in this study. Orcein staining was used to evaluate cell cycle-dependent modifications in nuclear configuration. The results showed that the percentages of oocytes displaying a normal configuration of chromosomes in metaphase II (MII) increased in the VEGF group (87.42%) compared to the control (83.89%). This result indicated that VEGF effectively improved the normal configuration of chromosomes.
Experimentation 5: Human recombinant VEGF165 was employed at 5 ng/ml in maturation media (TCM199+ bovine serum albumin, BSA) in this study. Immunofluorescence and confocal microscopy were used to evaluate microtubule organizing centers (MTOCs) translocation and the temporal and spatially redistribution ofα-tubulin. The results showed that the percentages of oocytes displaying a normal distribution ofα-tubulin and chromosomes in metaphase II (MII) significantly increased in the VEGF group (77.50%) compared to the control (62.60%)(P<0.01). VEGF promoted the MTOCs domains to disappear from the cortex and stimulated assembly ofα-tubulin around chromosome domains when germinal vesicle breakdown (GVBD) was commencing. These results showed that VEGF may improve the quality of nuclear maturation of ovine oocytes in vitro by the effects on the temporal and spatial translocation or redistribution of MTOC andα-tubulin.
Experimentation 6: Human recombinant VEGF165 was employed at 5 ng/ml in maturation media (TCM199+ bovine serum albumin, BSA) in this study. Immunofluorescence and confocal microscopy were used to evaluate the temporal and spatially redistribution of cortical granules (CGs). The results showed that the rate of oocytes with CGs transfering completely in cortex was significantly higher (79.24%) in the VEGF group than in the control group (60.97%)(P<0.01). VEGF may improve the quality of cytoplasmic maturation of ovine oocytes in vitro by the effects on the temporal and spatial translocation or redistribution of CGs.
1.2 The effect of VEGF on the ultrastructure change of ovine oocytes matured in vitro
Experimentation 7: Human recombinant VEGF165 was employed at 5 ng/ml in maturation media (TCM199+ bovine serum albumin, BSA) in this study. The results showed that the development and change of microvilli on the surface of oocytes could be affected with VEGF in the maturation media. VEGF could promote the oocytes absorbing nutrientsubstance and the communication. VEGF may effects the temporal and spatial translocation or redistribution of CGs. There were so many mitochondria with“cap”in the oocytes cytoplasm. The development and transfer of mitochondria was effected by VEGF. There were no remarkable effects of VEGF on the accumulation of cytoplasmic lipid droplet, but VEGF could avoide the integration of many droplets to bigger ones.
1.3 The effect of VEGF on the change of P44/p42 MAP kinases, Protein Kinase C and Tyrosine kinases of ovine oocytes matured in vitro
Experimentation 8: In this study, VEGF was supplied at 5 ng/ml in maturation media for determine the effect of it on the change of phosphorylation P44/p42 MAP kinases (ERKs), Protein Kinase C (PKC) and Tyrosine Kinases (PTKs) activity in ovine oocyte during maturation by ELISA in vitro. The results showed that: these three protein kinase took on fluctuant changes. The levels of phosphorylation ERKs in the VEGF treatment group were higher than that of the control group, especially at 16 hours and 20 hours (P<0.05). The levels of phosphorylation PTK in the VEGF treatment group were higher than that of the control group, especially at 16 hours 21 hours and 24 hours (P<0.05). The levels of phosphorylation PKC in the VEGF treatment group were higher than that of the control group too. VEGF was strongly enhanced the level of phosphorylation ERKs and PKC activity but reduced PTKs activity during the period of ovine oocyte maturation in vitro for improving the quality of oocytes.
1.4 Expression of VEGF and its receptors (Flt-1 and KDR/ Flk-1) in ovine oocytes matured in vitro
Experimentation 9: Human recombinant VEGF165 was employed at 5 ng/ml in maturation media (TCM199+ bovine serum albumin, BSA) in this study. Expression of VEGF and its receptors (Flt-1 and KDR/ Flk-1) mRNA in ovine oocytes matured in vitro by RT-PCR. The results showed that VEGF mRNA was expressed in cumulus cells and oocytes without cumulus cells at 0 hour、8hours and 24 hours, but it was highest in cumulus cells of the control group and in oocytes without cumulus cells of the treatment group at the 8 hours matured in vitro. Flt-1 mRNA was expressed in cumulus cells of the control group at 0 hour and 8 hours, and was not detect in the treatment group. Relative amount of Flt-1 mRNA for cumulus cells at 8 hours of control group was higher than that of 0 hour. Meanwhile, Flt-1 mRNA was expressed in oocytes without cumulus cells at 0 hour and 8 hours both in the control group and the treatment group. The Flt-1 mRNA expression at 0 hour was highest and took second place at 8 hours of the control group, the Flt-1 mRNA expression of the treatment at 8 hours was lowest. It was not detect Flt-1 mRNA expression in cumulus cells and oocytes without cumulus cells at 24 hours maturation. KDR/ Flk-1 mRNA was expressed in cumulus cells and oocytes without cumulus cells at 0 hour、8hours and 24 hours both in the control group and the treatment group. KDR/ Flk-1 mRNA expression was highest at both 8 hours in cumulus cells and 24 hours in oocytes without cumulus cells of the control group. There were weak KDR/ Flk-1 mRNA expression in cumulus cells of the treatment group at 8 hours and 24 hours.
Experimentation 10: Human recombinant VEGF165 was employed at 5 ng/ml in maturation media (TCM199+ bovine serum albumin, BSA) in this study. In the present study, ovine cumulus-oocyte complexes (COC) were matured in vitro in the treatment group with 5 ng/ml human recombinant VEGF165 in maturation media and the control group without VEGF, confocal microscopy and immunohistochemical staining methods were used to assess the location and expression of Flt-1 and KDR/ Flk-1 in the plasma membranes of cumulus cells and oocytes without cumulus cells at different maturation time (0hour、8hours and 24hours). The results showed that Flt-1 and KDR/ Flk-1 were expressed in cell plasma membranes of maturation oocytes without cumulus cells and cumulus cells at 0 hour、8hours and 24hours. Flt-1 and KDR/ Flk-1 were mainly detected in the cytoplasm close to the membrane both in immature and mature oocytes without cumulus cells. The staining for Flt-1 slightly increased in the control group compared to the treatment group in maturation oocytes without cumulus cells and cumulus cells. However, the staining for Flt-1 and KDR/ Flk-1 was slightly weaker in cell plasma membranes of oocytes without cumulus cells than in that of cumulus cells.
一、血管内皮生长因子对绵羊卵母细胞体外成熟、体外受精及胚胎发育的影响
试验1:不同浓度VEGF对绵羊胚胎体外发育的影响
在绵羊卵母细胞体外成熟培养液(TCM199+胎牛血清)、HSOF受精液及SOF胚胎发育液中添加不同剂量的VEGF(对照组0 ng/ml、试验组Ⅰ5 ng/ml和试验组Ⅱ10 ng/ml),研究其对卵母细胞成熟和早期胚胎发育的影响。结果显示:对照组、试验组Ⅰ、试验组Ⅱ卵母细胞成熟率分别是80.68%、86.09%和85.22%。试验组Ⅰ和试验组Ⅱ与对照组相比,极显著的提高了卵母细胞成熟率(P<0.01),但试验组Ⅰ和试验组Ⅱ之间差异不显著。试验组Ⅰ和试验组Ⅱ的卵裂率分别是75.18%和73.48%,高于对照组的69.38%,但差异不显著。试验组Ⅰ的桑葚胚率和囊胚率是45.45%和30.06%,极显著的高于对照组37.61%和23.65%(P<0.01);同时试验组Ⅱ的桑葚胚率和囊胚率是40.25%和27.80%,低于试验组Ⅰ,高于对照组,但差异不显著。结果表明:体外培养液中添加5ng/mlVEGF为适宜添加量,VEGF明显提高了受精卵发育到桑葚胚和囊胚的能力。
试验2:BSA成熟培养液中添加VEGF对绵羊卵母细胞体外成熟、体外受精及胚胎发育的影响
本试验采用在成分相对明确的BSA成熟培养液系统中,添加不同浓度VEGF,检测对卵母细胞成熟和胚胎发育的作用。成熟培养液(TCM199+BSA)中分别添加0 ng/mlVEGF对照组、5 ng/ml、10 ng/ml的VEGF试验组卵母细胞成熟培养后,经体外受精和体外培养。结果显示:试验组Ⅰ和试验组Ⅱ的成熟率分别是83.98%和80.23%,对照组是75.76%。试验组Ⅰ和试验组Ⅱ与对照组相比,极显著的提高了绵羊卵母细胞的成熟率(P<0.01),并且试验组Ⅰ和试验组Ⅱ之间差异显著(P<0.05)。试验组Ⅰ的卵裂率是79.39%,高于试验组Ⅱ和对照组的72.24%和75.85%,差异不显著。试验组Ⅰ桑葚胚率是45.03%,明显高于试验组Ⅱ和对照组38.85%和38.94%的桑葚胚率,差异不显著。试验组Ⅰ囊胚率是23.54%,极显著高于对照组的18.09%(P<0.01);试验组Ⅱ囊胚率是21.05%,高于对照组Ⅰ的18.09%,差异不显著。结果表明:BSA成熟培养液中添加5ng/ml VEGF为适宜添加量,对绵羊卵母细胞体外胚胎的发育有积极的促进作用。
试验3:VEGF添加对绵羊卵母细胞体外受精多精入卵的影响
在绵羊卵母细胞体外成熟培养液(TCM199+BSA)中添加不同剂量的VEGF(对照组0 ng/ml和试验组5 ng/ml)成熟培养,经体外受精培养后,地衣红染色结果显示:试验组和对照组的受精率分别是83.86%和75.75%,多精入卵率分别是7.68%和12.64%,未受精率是8.47%和11.60%。试验组受精率极显著高于对照组(P<0.01);试验组多精入卵率极显著低于对照组(P<0.01);试验组的未受精率显著低于对照组(P<0.05)。结果表明:VEGF明显降低了多精入卵率,有效的抑制了绵羊卵母细胞受精过程中的多精入卵现象的发生。
二、VEGF促进绵羊卵母细胞体外成熟的机理研究
1、VEGF对绵羊卵母细胞体外成熟过程中细胞核成熟和细胞质成熟的影响
试验4:在绵羊卵母细胞体外成熟培养液(TCM199+BSA)中添加不同剂量的VEGF(对照组0 ng/ml和试验组5 ng/ml)进行成熟培养,再采用地衣红染色技术,研究VEGF对绵羊卵母细胞体外成熟过程中染色体形态的影响。结果显示:试验组拥有正常染色体成熟卵母细胞的成熟率是87.42%,高于对照组的83.89%。结果表明:VEGF对卵母细胞体外成熟和维持染色体正常形态具有一定的促进作用。
试验5:在BSA成熟培养系统中成熟培养后,采用免疫细胞化学和激光共聚焦显微技术,研究VEGF对绵羊卵母细胞体外成熟过程中α-tubulin蛋白和微管组织中心(Microtubule Organizing Centers,MTOCs)时空迁移和重新组装的影响。结果显示:试验组与对照组相比,极大的促进了α-tubulin从微管组织中心向染色体的空间迁移和重新组装。同时试验得出,试验组和对照组的微管蛋白和MII期染色体的正常分布率分别是77.50%和62.60%。试验组与对照组相比,极显著的提高了微管蛋白和MII期染色体的正常分布率(P<0.01)。结果表明:VEGF促进了MTOCs从胞内和皮质区的消失,并加速了α-tubulin重新分配和向染色体的聚集,有效的提高了卵母细胞核成熟质量。
试验6:在BSA成熟培养系统中成熟培养后,采用免疫细胞化学和激光共聚焦显微技术,研究VEGF对绵羊卵母细胞体外成熟过程中皮质颗粒(Cortical Granule,CGs)时空迁移和重新组装的影响。结果显示:试验组与对照组相比,极大的促进了CGs从胞质向皮质区的时空迁移。试验组和对照组的皮质颗粒正常迁移分布率分别为79.24%和60.97%。试验组与对照组相比,极显著的提高了皮质颗粒正常迁移分布率(P<0.01)。结果表明:VEGF通过促进绵羊卵母细胞成熟过程中CGs的时空迁移,对绵羊卵母细胞胞质成熟具有积极促进作用。
2、VEGF对绵羊卵母细胞体外成熟过程中细胞超微结构变化的影响
试验7:在绵羊卵母细胞体外成熟培养液(TCM199+BSA)中添加不同剂量的VEGF(对照组0 ng/ml和试验组5 ng/ml)进行成熟培养,再结合透射电镜技术,研究VEGF对绵羊卵母细胞体外成熟过程中细胞超微结构变化的影响。结果显示:①VEGF有效促进了微绒毛的发育和变化,增加了游离端斜行插入透明带微绒毛的数量,促进了细胞内外物质交流和养分的吸收;②VEGF促进了皮质颗粒在卵母细胞成熟培养过程中向皮质区迁移的时间和空间变化;③发现特征性绵羊卵母细胞线粒体――带帽状线粒体,并且VEGF对线粒体的迁移有一定的促进作用;④VEGF的添加对卵母细胞成熟过程中脂滴数量的增加没有显著的作用,但VEGF减少了小脂滴聚集为大脂滴。
3、VEGF对绵羊卵母细胞体外成熟过程中胞内磷酸化P44/p42 MAP kinases、PKC和PTK活性变化的影响
试验8:在绵羊卵母细胞体外成熟培养液(TCM199+BSA)中添加不同剂量的VEGF(对照组0 ng/ml和试验组5 ng/ml)进行成熟培养,再结合酶联免疫技术,检测胞内磷酸化P44/p42 MAP kinases、PKC和PTK活性的变化。结果显示:绵羊卵母细胞成熟过程中三种磷酸化激酶活性都呈波动变化,试验组的P44/p42 MAP kinases、PKC和PTK相对含量始终高于对照组相对含量。成熟培养16小时和20小时时,试验组P44/p42 MAP kinases(Erk1和Erk2)含量显著高于对照组(P<0.05);成熟培养16、21小时和24小时时,试验组PTK含量显著升高于对照组(P<0.05)。结果表明:VEGF添加到绵羊卵母细胞成熟培养液中,改变了PTK磷酸化水平,进一步引起信号传递分子MAP kinase和PKC的磷酸化,从而有效促进了绵羊卵母细胞体外成熟。
4、VEGF及其受体KDR/Flk-1和Flt-1在绵羊卵母细胞体外成熟过程中的表达
试验9:在绵羊卵母细胞体外成熟培养液(TCM199+BSA)中添加不同剂量的VEGF(对照组0 ng/ml和试验组5 ng/ml)进行成熟培养,再结合RT-PCR技术,研究VEGF及其受体KDR/Flk-1和Flt-1mRNA在绵羊卵母细胞体外成熟过程中颗粒细胞和卵母细胞细胞中的表达。结果显示:①卵母细胞培养前VEGF mRNA在卵母细胞中就有表达。在整个成熟过程中对照组中其表达一直持续,但比培养前的表达量有所下降;在试验组中,VEGF mRNA在卵母细胞中的表达呈下降趋势,到成熟培养24小时时表达量微弱;卵母细胞培养前VEGF mRNA在颗粒细胞中有表达。到培养8小时时,对照组表达量升高,但后期表达量明显下降。试验组在培养8小时时表达量就已经下降,24小时时持续低水平表达。②卵母细胞培养前Flt-1 mRNA在卵母细胞中有微弱表达,随着培养时间的延续表达量明显下降。培养8小时和24小时对照组比试验组表达强,到24小时试验组几乎检测不到Flt-1 mRNA的表达;卵母细胞培养前Flt-1 mRNA在颗粒细胞中有表达,到8小时时对照组表达加强,随培养时间延续其表达量下降,直至24小时检测不到。试验组从培养8小时开始就几乎检测不到Flt-1 mRNA的表达。③卵母细胞培养前KDR/Flk-1 mRNA在卵母细胞中有微弱表达,随着培养时间的延续,无论是试验组还是对照组其表达量都明显上升;卵母细胞培养前KDR/Flk-1 mRNA在颗粒细胞中有强表达,随培养时间的延续其表达量在对照组培养8小时时加强,但在试验组中减弱,培养到24小时时,两组表达量都很微弱。结果表明:外源VEGF的加入,改变了卵母细胞和颗粒细胞中VEGF及其受体KDR/Flk-1和Flt-1 mRNA的表达。
试验10:结合免疫细胞化学和激光共聚焦显微技术,研究KDR/Flk-1和Flt-1蛋白在卵母细胞成熟观过程中颗粒细胞和卵母细胞中的表达。结果显示:绵羊卵母细胞成熟培养过程中,无论是在卵母细胞膜表面还是在颗粒细胞膜表面都检测到KDR/Flk-1和Flt-1蛋白的表达。
To investigate the effect of vascular endothelial growth factor (VEGF) on the ovine oocytes maturation and the early development of embryo in vitro, a series of ten experiments were conducted with VEGF supplemented to the maturation medium、the fertilization medium and the culture medium respectively. To show the mechanism of VEGF on promoting ovine oocyte maturation in virto by evaluate cell cycle-dependent modifications in cell configuration, cell framework, the change of active MAPK/PKC/PTK in oocyte, the expression of VEGF and its receptors KDR/Flk-1 and Flt-1 in ovine oocytes undergoing in vitro maturation.
1、The effect of VEGF on the ovine oocytes maturation and the early development of embryo in vitro
Experimentation 1: Human recombinant VEGF165 was employed at 5 ng/ml and 10 ng/ml in maturation media(TCM199+fetal bovine serum, FBS), HSOF fertilization media and SOF culture media in this study. The results showed that the maturation rate was increased significantly (p <0.01) from 80.68% in the control(0 ng/ml VEGF) to 86.09% and 85.22% in the treatment groupⅠ(5 ng/ml VEGF)and the treatment groupⅡ(10 ng/ml VEGF) respectively. The cleavage rate was increased from 69.38% in the control group to 75.18% and 73.48% (p>0.05) in the treatment groupⅠand the treatment groupⅡrespectively. The development rates of morulae and blastocyst in the treatment groupⅠ(45.45% and 30.06%) were higher significantly (p <0.01)than that of the control group (37.61% and 23.65%). And the development rates of morulae and blastocyst in the treatment groupⅡ(40.25% and 27.80%)were lower than that of the treatment groupⅠ(P>0.05) and higher than that of the control group(P>0.05). These results indicated that maturation medium, fertilization medium and the culture medium with 5 ng/ml of recombinant human VEGF165 significantly improved the maturation and fertilization of ovine oocytes and consequently the rate of embryos development were markedly enhanced. VEGF may be one of the important regular factors in system of maturation and fertilization of ovine oocyte and the early development of ovine embryo in vitro.
Experimentation 2: Human recombinant VEGF165 was employed at 5 ng/ml and 10 ng/ml in maturation media(TCM199+ bovine serum albumin, BSA), HSOF fertilization media and SOF culture media in this study. The results showed that the maturation rate was increased significantly (p <0.01) from 75.76% in the control (0 ng/ml VEGF) to 83.98% and 80.23% in the treatment groupⅠ(5 ng/ml VEGF)and the treatment groupⅡ(10 ng/ml VEGF) respectively. The cleavage rate was increased from 75.85% in the control group to 79.39%(p>0.05) in the treatment groupⅠ.The development rates of morulae and blastocyst in the treatment groupⅠ(45.03% and 23.54%) were higher significantly (p <0.01)than that of the control group (38.94% and 18.09%). And the development rates of morulae and blastocyst in the treatment groupⅡ(38.85% and 21.05%)were lower than that of the treatment groupⅠ(P>0.05) and higher than that of the control group(P>0.05). These results indicated that BSA maturation medium with 5 ng/ml of recombinant human VEGF165 significantly improved the maturation and fertilization of ovine oocytes and consequently the rate of embryos development were markedly enhanced also. VEGF may be one of the important regular factors in system of maturation and fertilization of ovine oocyte and the early development of ovine embryo in vitro.
Experimentation 3: Human recombinant VEGF165 was employed at 5 ng/ml in maturation media(TCM199+ bovine serum albumin, BSA) in this study. The results showed that the fertilization rate was increased significantly (p <0.01) from 75.75% in the control (0 ng/ml VEGF) to 83.86% in the treatment group (5 ng/ml VEGF) and the polyspermy rate was decreased significantly (p <0.01)from 12.64% in the control to 7.68% in the treatment group. The no fertilization rate was decreased (p <0.05) from 11.60% in the control to 8.47% in the treatment group. These results indicated that VEGF obviously decreased the polyspermy rate and bated the phenomenon of polyspermy in the process of ovine oocytes IVF.
1、The mechanism of VEGF on promoting ovine oocyte maturation in vitro
1.1 The effect of VEGF on the nuclear and cytoplasmic maturation of ovine oocytes matured in vitro
Experimentation 4: Human recombinant VEGF165 was employed at 5 ng/ml in maturation media (TCM199+ bovine serum albumin, BSA) in this study. Orcein staining was used to evaluate cell cycle-dependent modifications in nuclear configuration. The results showed that the percentages of oocytes displaying a normal configuration of chromosomes in metaphase II (MII) increased in the VEGF group (87.42%) compared to the control (83.89%). This result indicated that VEGF effectively improved the normal configuration of chromosomes.
Experimentation 5: Human recombinant VEGF165 was employed at 5 ng/ml in maturation media (TCM199+ bovine serum albumin, BSA) in this study. Immunofluorescence and confocal microscopy were used to evaluate microtubule organizing centers (MTOCs) translocation and the temporal and spatially redistribution ofα-tubulin. The results showed that the percentages of oocytes displaying a normal distribution ofα-tubulin and chromosomes in metaphase II (MII) significantly increased in the VEGF group (77.50%) compared to the control (62.60%)(P<0.01). VEGF promoted the MTOCs domains to disappear from the cortex and stimulated assembly ofα-tubulin around chromosome domains when germinal vesicle breakdown (GVBD) was commencing. These results showed that VEGF may improve the quality of nuclear maturation of ovine oocytes in vitro by the effects on the temporal and spatial translocation or redistribution of MTOC andα-tubulin.
Experimentation 6: Human recombinant VEGF165 was employed at 5 ng/ml in maturation media (TCM199+ bovine serum albumin, BSA) in this study. Immunofluorescence and confocal microscopy were used to evaluate the temporal and spatially redistribution of cortical granules (CGs). The results showed that the rate of oocytes with CGs transfering completely in cortex was significantly higher (79.24%) in the VEGF group than in the control group (60.97%)(P<0.01). VEGF may improve the quality of cytoplasmic maturation of ovine oocytes in vitro by the effects on the temporal and spatial translocation or redistribution of CGs.
1.2 The effect of VEGF on the ultrastructure change of ovine oocytes matured in vitro
Experimentation 7: Human recombinant VEGF165 was employed at 5 ng/ml in maturation media (TCM199+ bovine serum albumin, BSA) in this study. The results showed that the development and change of microvilli on the surface of oocytes could be affected with VEGF in the maturation media. VEGF could promote the oocytes absorbing nutrientsubstance and the communication. VEGF may effects the temporal and spatial translocation or redistribution of CGs. There were so many mitochondria with“cap”in the oocytes cytoplasm. The development and transfer of mitochondria was effected by VEGF. There were no remarkable effects of VEGF on the accumulation of cytoplasmic lipid droplet, but VEGF could avoide the integration of many droplets to bigger ones.
1.3 The effect of VEGF on the change of P44/p42 MAP kinases, Protein Kinase C and Tyrosine kinases of ovine oocytes matured in vitro
Experimentation 8: In this study, VEGF was supplied at 5 ng/ml in maturation media for determine the effect of it on the change of phosphorylation P44/p42 MAP kinases (ERKs), Protein Kinase C (PKC) and Tyrosine Kinases (PTKs) activity in ovine oocyte during maturation by ELISA in vitro. The results showed that: these three protein kinase took on fluctuant changes. The levels of phosphorylation ERKs in the VEGF treatment group were higher than that of the control group, especially at 16 hours and 20 hours (P<0.05). The levels of phosphorylation PTK in the VEGF treatment group were higher than that of the control group, especially at 16 hours 21 hours and 24 hours (P<0.05). The levels of phosphorylation PKC in the VEGF treatment group were higher than that of the control group too. VEGF was strongly enhanced the level of phosphorylation ERKs and PKC activity but reduced PTKs activity during the period of ovine oocyte maturation in vitro for improving the quality of oocytes.
1.4 Expression of VEGF and its receptors (Flt-1 and KDR/ Flk-1) in ovine oocytes matured in vitro
Experimentation 9: Human recombinant VEGF165 was employed at 5 ng/ml in maturation media (TCM199+ bovine serum albumin, BSA) in this study. Expression of VEGF and its receptors (Flt-1 and KDR/ Flk-1) mRNA in ovine oocytes matured in vitro by RT-PCR. The results showed that VEGF mRNA was expressed in cumulus cells and oocytes without cumulus cells at 0 hour、8hours and 24 hours, but it was highest in cumulus cells of the control group and in oocytes without cumulus cells of the treatment group at the 8 hours matured in vitro. Flt-1 mRNA was expressed in cumulus cells of the control group at 0 hour and 8 hours, and was not detect in the treatment group. Relative amount of Flt-1 mRNA for cumulus cells at 8 hours of control group was higher than that of 0 hour. Meanwhile, Flt-1 mRNA was expressed in oocytes without cumulus cells at 0 hour and 8 hours both in the control group and the treatment group. The Flt-1 mRNA expression at 0 hour was highest and took second place at 8 hours of the control group, the Flt-1 mRNA expression of the treatment at 8 hours was lowest. It was not detect Flt-1 mRNA expression in cumulus cells and oocytes without cumulus cells at 24 hours maturation. KDR/ Flk-1 mRNA was expressed in cumulus cells and oocytes without cumulus cells at 0 hour、8hours and 24 hours both in the control group and the treatment group. KDR/ Flk-1 mRNA expression was highest at both 8 hours in cumulus cells and 24 hours in oocytes without cumulus cells of the control group. There were weak KDR/ Flk-1 mRNA expression in cumulus cells of the treatment group at 8 hours and 24 hours.
Experimentation 10: Human recombinant VEGF165 was employed at 5 ng/ml in maturation media (TCM199+ bovine serum albumin, BSA) in this study. In the present study, ovine cumulus-oocyte complexes (COC) were matured in vitro in the treatment group with 5 ng/ml human recombinant VEGF165 in maturation media and the control group without VEGF, confocal microscopy and immunohistochemical staining methods were used to assess the location and expression of Flt-1 and KDR/ Flk-1 in the plasma membranes of cumulus cells and oocytes without cumulus cells at different maturation time (0hour、8hours and 24hours). The results showed that Flt-1 and KDR/ Flk-1 were expressed in cell plasma membranes of maturation oocytes without cumulus cells and cumulus cells at 0 hour、8hours and 24hours. Flt-1 and KDR/ Flk-1 were mainly detected in the cytoplasm close to the membrane both in immature and mature oocytes without cumulus cells. The staining for Flt-1 slightly increased in the control group compared to the treatment group in maturation oocytes without cumulus cells and cumulus cells. However, the staining for Flt-1 and KDR/ Flk-1 was slightly weaker in cell plasma membranes of oocytes without cumulus cells than in that of cumulus cells.
引文
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