Placental expression of angiogenesis-related genes and their receptors in IUGR pregnancies: correlation with fetoplacental and maternal parameters

<b>Objectives:</b> Aberrations in placental vascular development compromising fetal supply of oxygen and essential nutrients can be a significant contributor to intrauterine growth restriction (IUGR). The development of placental vascular tree is under the influence of two families of growth factors, namely the vascular endothelial growth factor (VEGF) family and angiopoietin/TEK family. In this study, we have examined the expression of angiogenesis-related growth factors, mainly VEGF family and angiopoietin-TEK (endothelial-specific receptor tyrosine kinase) family genes in placentae from IUGR pregnancies uncomplicated by preeclampsia (PE) compared to normal pregnancies. <b>Methods:</b> Placentae from normotensive IUGR (<i>n</i> = 42) and appropriate for gestational age (AGA) pregnancies (<i>n</i> = 47) were collected and examined histologically. Clinical parameters were obtained from the medical records. Real-time quantitative PCR was performed to assess placental transcript abundance of <i>VEGF</i>, <i>PGF</i>, <i>FLT1</i>, <i>ANGPT1</i>, <i>ANGPT2</i>, and <i>TEK</i> normalized to a panel of reference genes. Associations of placental transcript abundance of the genes with maternal, placental, and neonatal parameters were tested. <b>Results:</b> Placental transcript abundance for <i>VEGF</i> (relative expression 10.81 versus 12.98, <i>p</i> &lt; .001), <i>PGF</i> (12.14 versus 13.8, <i>p</i> &lt; .001) and <i>ANGPT2</i> (3.67 versus 9.55, <i>p</i> = .002) were significantly lower in IUGR placentae compared to AGA. The transcript level of <i>VEGF</i> showed significant negative correlation with birth weight (<i>r</i> = −0.419, <i>p</i> = .006), placental weight (<i>r</i> = −0.318, <i>p</i> = .040), placental length (<i>r</i> = −0.389, <i>p</i> = .011) and breadth (r = −0.308, <i>p</i> = .047) only in the IUGR group. Presence of histopathological features of hypoxia correlated with significantly higher transcript levels of <i>PGF</i> in IUGR placentae (12.6 versus 10.9, <i>p</i> = .046). <b>Conclusion:</b> The low levels of <i>VEGF</i> transcripts may be responsible for the impaired angiogenesis in IUGR placentae. The significance of higher relative expression of <i>PGF</i> in the presence of chronic hypoxia needs to be explored.

<b>研究目的：</b> 胎盘血管发育异常导致胎儿氧气及必需营养物质供给受损，是宫内生长受限（intrauterine growth restriction, IUGR）的重要致病因素之一。胎盘血管树的发育受两类生长因子家族调控，即血管内皮生长因子（vascular endothelial growth factor, VEGF）家族及血管生成素/TEK家族。本研究对比分析了无子痫前期（preeclampsia, PE）并发症的宫内生长受限妊娠与正常妊娠的胎盘组织，检测其中血管生成相关生长因子——主要为VEGF家族及血管生成素-TEK（内皮特异性受体酪氨酸激酶，endothelial-specific receptor tyrosine kinase）家族——的基因表达水平。
<b>研究方法：</b> 本研究收集了42例血压正常的宫内生长受限妊娠胎盘组织（<i>n</i> = 42）与47例适于胎龄儿（appropriate for gestational age, AGA）妊娠胎盘组织（<i>n</i> = 47），并行组织学检测。从病历中提取临床参数信息。采用实时定量PCR（real-time quantitative PCR）检测胎盘组织中<i>VEGF</i>、<i>PGF</i>、<i>FLT1</i>、<i>ANGPT1</i>、<i>ANGPT2</i>及<i>TEK</i>的转录本丰度，以一组内参基因进行标准化校正。随后分析上述基因的胎盘转录本丰度与产妇、胎盘及新生儿相关参数的相关性。
<b>研究结果：</b> 与适于胎龄儿妊娠胎盘组织相比，宫内生长受限妊娠胎盘组织中<i>VEGF</i>（相对表达量10.81 vs 12.98，<i>p</i> &lt; 0.001）、<i>PGF</i>（12.14 vs 13.8，<i>p</i> &lt; 0.001）及<i>ANGPT2</i>（3.67 vs 9.55，<i>p</i> = 0.002）的转录本丰度均显著降低。仅在宫内生长受限组中，<i>VEGF</i>的转录水平与新生儿出生体重（<i>r</i> = -0.419，<i>p</i> = 0.006）、胎盘重量（<i>r</i> = -0.318，<i>p</i> = 0.040）、胎盘长度（<i>r</i> = -0.389，<i>p</i> = 0.011）及胎盘宽度（<i>r</i> = -0.308，<i>p</i> = 0.047）呈显著负相关。宫内生长受限胎盘组织中若存在缺氧相关组织病理学特征，则<i>PGF</i>的转录水平显著升高（12.6 vs 10.9，<i>p</i> = 0.046）。
<b>研究结论：</b> <i>VEGF</i>转录本水平降低可能是宫内生长受限胎盘组织血管生成受损的原因。慢性缺氧状态下<i>PGF</i>相对表达升高的临床意义仍有待进一步探究。