Chen Zhen-Yan, Li Jing, Huang Guang-Ying
Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
J Huazhong Univ Sci Technolog Med Sci. 2013 Apr;33(2):293-302. doi: 10.1007/s11596-013-1114-y. Epub 2013 Apr 17.
Interactions of vascular endothelial growth factor (VEGF) with receptors VEGFR1/Flt1 and VEGFR2/Flk1, and those of angiopoietins (Ang-1, Ang-2) with receptor Tie2 play important roles in placental angiogenesis. This study investigated vascular morphology and expression of these angiogenic factors in rat placenta on the day 15, 18, 21 of gestation (D15, D18 and D21). The rats were randomly assigned into 3 groups: normal group, model group [fetal growth restriction (FGR) model], and Bushen Yiqi Huoxue (BYHR) recipe treatment group (BYHR group, the pregnant rats with FGR were treated with BYHR recipe). Morphological analysis indicated that during initial villous formation, fetal nucleated erythrocytes (FNEs) appeared in maternal blood sinus (MBS). Subsequently, FNEs were surrounded by endothelial cells to form fetal capillary (FC) and then by trophoblast cells to form villi. As pregnancy proceeded, FC density increased progressively with increasing endothelial identification staining (EIS) in normal and BYHR groups. Whereas, villous formation was suppressed, normal increase in FC density was impaired and EIS was weakened in model group. Quantitative PCR analysis showed that VEGF and Flk1 mRNA increased over gestation in all groups, indicating that VEGF might play a pivotal role in FC growth during late gestation. VEGF mRNA was increased on D15, while decreased on D21 in model group as compared with normal group and BYHR group. Immunohistochemically, Ang-2 protein was highly expressed in FNEs, gradually disappeared as villi matured, and decreased over gestation in all groups, indicating that Ang-2 might play a pivotal role in villous formation, which was further supported by decreased Ang-2 mRNA and protein expression in model group on D15. Ang-1 mRNA, Tie2 mRNA and Ang-1/Ang-2 ratio increased from D15 to D18 in all groups as placenta matured. Ang-1 mRNA, Tie2 mRNA and Ang-1/Ang-2 ratio were decreased on D18 in model group as compared with normal and BYHR groups, indicating delayed maturity of FGR placenta. Alterations in angiogenic factors may result in altered placental vasculature and cause placental insufficiency. BYHR recipe could balance the angiogenic factors to promote the formation and maturation of FGR placental vasculature.
血管内皮生长因子（VEGF）与受体VEGFR1/Flt1和VEGFR2/Flk1的相互作用，以及血管生成素（Ang-1、Ang-2）与受体Tie2的相互作用在胎盘血管生成中起重要作用。本研究调查了妊娠第15、18、21天（D15、D18和D21）大鼠胎盘的血管形态以及这些血管生成因子的表达。大鼠被随机分为3组：正常组、模型组[胎儿生长受限（FGR）模型]和补肾益气活血（BYHR）方剂治疗组（BYHR组，对患有FGR的孕鼠用BYHR方剂治疗）。形态学分析表明，在初始绒毛形成过程中，胎儿有核红细胞（FNE）出现在母体血窦（MBS）中。随后，FNE被内皮细胞包围形成胎儿毛细血管（FC），然后被滋养层细胞包围形成绒毛。随着妊娠进展，正常组和BYHR组中FC密度随着内皮识别染色（EIS）增加而逐渐升高。然而，模型组中绒毛形成受到抑制，FC密度正常增加受损且EIS减弱。定量PCR分析显示，所有组中VEGF和Flk1 mRNA在整个妊娠期均增加，表明VEGF可能在妊娠晚期FC生长中起关键作用。与正常组和BYHR组相比，模型组中VEGF mRNA在D15时增加，而在D21时降低。免疫组织化学显示，Ang-2蛋白在FNE中高表达，随着绒毛成熟逐渐消失，且在所有组中随妊娠进展而降低，表明Ang-2可能在绒毛形成中起关键作用，D15时模型组中Ang-2 mRNA和蛋白表达降低进一步支持了这一点。随着胎盘成熟，所有组中Ang-1 mRNA、Tie2 mRNA和Ang-1/Ang-2比值从D15到D18均增加。与正常组和BYHR组相比，模型组中D18时Ang-1 mRNA、Tie2 mRNA和Ang-1/Ang-2比值降低，表明FGR胎盘成熟延迟。血管生成因子的改变可能导致胎盘血管系统改变并引起胎盘功能不全。BYHR方剂可平衡血管生成因子，促进FGR胎盘血管系统的形成和成熟。
