Su Emily J, Xin Hong, Yin Ping, Dyson Matthew, Coon John, Farrow Kathryn N, Mestan Karen K, Ernst Linda M
Department of Obstetrics and Gynecology (E.J.S., H.X., P.Y., M.D., J.C.), Division of Maternal-Fetal Medicine and/or Division of Reproductive Science in Medicine, and Department of Pathology (L.M.E.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; and Department of Pediatrics (K.N.F., K.K.M.), Division of Neonatology, Northwestern University Feinberg School of Medicine and Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois 60611.
J Clin Endocrinol Metab. 2015 Jan;100(1):E30-40. doi: 10.1210/jc.2014-2385.
Fetal growth restriction with abnormal umbilical artery Doppler velocimetry (FGRadv), reflective of elevated fetoplacental vascular resistance, is associated with increased risks of fetal morbidity and mortality even in comparison to those of growth-restricted fetuses with normal placental blood flow. One major cause of this abnormally elevated fetoplacental vascular resistance is the aberrantly formed, thin, elongated villous vessels that are seen in FGRadv placentas.
The purpose of this study was to determine the role of fetoplacental endothelial cells (ECs) in angiogenesis in normal pregnancies and in those complicated by FGRadv.
Human placental specimens were obtained from FGRadv and gestational age-matched, appropriately grown control pregnancies for EC isolation/culture and for immunohistochemical studies. Additional mechanistic studies were performed on ECs isolated from subjects with term, uncomplicated pregnancies.
We evaluated tube formation and differential angiogenic gene expression in FGRadv and control ECs, and we used ECs from uncomplicated pregnancies to further elucidate the molecular mechanisms by which angiogenesis is impaired in FGRadv pregnancies.
Tube formation assays showed that FGRadv ECs demonstrate fewer branch points and total length compared with those from gestational age-matched controls, and this defect was not rescued by exposure to hypoxia. FGRadv ECs also demonstrated lower aryl hydrocarbon receptor nuclear translocator (ARNT) expression. ARNT knockdown resulted in suppression of key angiogenic genes including vascular endothelial growth factor A expression and led to deficient tube formation.
ARNT expression in the placental vasculature mediates key angiogenic expression and fetoplacental EC angiogenesis, and low ARNT expression in FGRadv ECs appears to be a key factor in deficient angiogenesis. This, in turn, results in malformed thin villous vessels that structurally contribute to the abnormally elevated fetoplacental vascular resistance that is associated with high morbidity and mortality in fetal growth restriction.
脐动脉多普勒测速异常的胎儿生长受限（FGRadv）反映了胎儿胎盘血管阻力升高，即使与胎盘血流正常的生长受限胎儿相比，其胎儿发病和死亡风险也更高。这种胎儿胎盘血管阻力异常升高的一个主要原因是FGRadv胎盘绒毛血管形态异常、纤细且拉长。
本研究的目的是确定胎儿胎盘内皮细胞（ECs）在正常妊娠和合并FGRadv的妊娠中血管生成中的作用。
从FGRadv和孕周匹配、生长正常的对照妊娠中获取人胎盘标本，用于EC分离/培养和免疫组织化学研究。对足月、无并发症妊娠受试者分离的ECs进行了额外的机制研究。
我们评估了FGRadv和对照ECs中的管形成和差异血管生成基因表达，并使用无并发症妊娠的ECs进一步阐明FGRadv妊娠中血管生成受损的分子机制。
管形成试验表明，与孕周匹配的对照组相比，FGRadv ECs的分支点和总长度更少，且这种缺陷不会因缺氧而得到改善。FGRadv ECs的芳烃受体核转运蛋白（ARNT）表达也较低。ARNT敲低导致包括血管内皮生长因子A表达在内的关键血管生成基因受到抑制，并导致管形成不足。
胎盘血管系统中的ARNT表达介导关键的血管生成表达和胎儿胎盘EC血管生成，FGRadv ECs中ARNT表达低似乎是血管生成不足的关键因素。这反过来又导致绒毛血管畸形、纤细，在结构上导致胎儿胎盘血管阻力异常升高，这与胎儿生长受限的高发病率和死亡率相关。
