Suzuki Hirotada, Ohkuchi Akihide, Matsubara Shigeki, Takei Yuji, Murakami Masato, Shibuya Masabumi, Suzuki Mitsuaki, Sato Yasufumi
Department of Obstetrics and Gynecology, Jichi Medical University School of Medicine, Tochigi, Japan.
Hypertension. 2009 Nov;54(5):1129-35. doi: 10.1161/HYPERTENSIONAHA.109.134668. Epub 2009 Sep 28.
The first aim of our study was to develop a pregnant mouse model for preeclampsia using adenoviral vector containing mouse full-length soluble fms-like tyrosine kinase 1 (sFlt-1) but not truncated sFlt-1. The second aim was to evaluate effects of recombinant mouse (rm) vascular endothelial growth factor (VEGF) and rm placental growth factor (PlGF) on a preeclampsia model induced by adenoviral vector containing mouse full-length sFlt-1. We injected adenoviral vector containing mouse full-length sFlt-1 on day 8.5 or 9.5 of gestation into pregnant Institute of Cancer Research mice, resulting in hypertension, proteinuria, and similar glomerular histological changes as those seen in human preeclamptic women with glomerular endotheliosis on day 16.5 or 17.5 of gestation. The preeclampsia models were treated with 100 microg/kg of rmVEGF164 (n=5), 100 microg/kg of rmPlGF-2 (n=5), or vehicle (n=7) twice a day for 2 days IP. The rmVEGF164 treatment significantly decreased the mean blood pressure on day 16.5 or 17.5 of gestation compared with the vehicle treatment (85+/-4 versus 97+/-2 mm Hg; P=0.018). The rmPlGF-2 treatment also significantly decreased the mean blood pressure on day 16.5 or 17.5 of gestation compared with the vehicle treatment (86+/-3 versus 97+/-2 mm Hg; P=0.018). However, proteinuria was not affected by either rmVEGF164 or rmPlGF-2. In conclusion, we, for the first time, created a mouse preeclampsia model using mouse full-length sFlt-1. VEGF and PlGF may be promising for ameliorating hypertension in women with preeclampsia. Additional study of PlGF as a potential drug for preeclampsia is warranted.
我们研究的首要目标是利用包含小鼠全长可溶性fms样酪氨酸激酶1（sFlt-1）而非截短型sFlt-1的腺病毒载体，开发一种子痫前期的孕鼠模型。第二个目标是评估重组小鼠（rm）血管内皮生长因子（VEGF）和rm胎盘生长因子（PlGF）对由包含小鼠全长sFlt-1的腺病毒载体诱导的子痫前期模型的影响。我们在妊娠第8.5天或9.5天，将包含小鼠全长sFlt-1的腺病毒载体注射到妊娠的癌症研究所小鼠体内，在妊娠第16.5天或17.5天时，导致高血压、蛋白尿以及与患有肾小球内皮病变的人类子痫前期女性相似的肾小球组织学变化。子痫前期模型每天两次腹腔注射100微克/千克的rmVEGF164（n = 5）、100微克/千克的rmPlGF-2（n = 5）或赋形剂（n = 7），持续2天。与赋形剂治疗相比，rmVEGF164治疗在妊娠第16.5天或17.5天时显著降低了平均血压（85±4对97±2毫米汞柱；P = 0.018）。与赋形剂治疗相比，rmPlGF-2治疗在妊娠第16.5天或17.5天时也显著降低了平均血压（86±3对97±2毫米汞柱；P = 0.018）。然而，rmVEGF164或rmPlGF-2均未影响蛋白尿。总之，我们首次利用小鼠全长sFlt-1创建了小鼠子痫前期模型。VEGF和PlGF可能有望改善子痫前期女性的高血压。有必要进一步研究PlGF作为子痫前期潜在药物的作用。
