Inhibition of Trophoblast-Induced Spiral Artery Remodeling Reduces Placental Perfusion in Rat Pregnancy
Inhibition of Trophoblast-Induced Spiral Artery Remodeling Reduces Placental Perfusion in Rat Pregnancy
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DOI：
10.1161/hypertensionaha.110.153163
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发表时间：
2010-08
期刊：
影响因子：
8.3
通讯作者：
S. Verlohren;N. Geusens;J. Morton;Iris Verhaegen;L. Hering;F. Herse;J. Dudenhausen;D. Muller;F. Luft;Judith E. Cartwright;S. Davidge;R. Pijnenborg;R. Dechend
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作者：
S. Verlohren;N. Geusens;J. Morton;Iris Verhaegen;L. Hering;F. Herse;J. Dudenhausen;D. Muller;F. Luft;Judith E. Cartwright;S. Davidge;R. Pijnenborg;R. Dechend
携带人血管紧张素原和人肾素基因的大鼠在妊娠期出现先兆子痫的特征。先兆子痫大鼠表现出更深的滋养层浸润与子宫多普勒阻力指数降低。强力霉素抑制基质金属蛋白酶活性。我们检验了基质金属蛋白酶抑制剂降低滋养层细胞浸润并随后改变胎盘灌注的假设。先兆子痫和妊娠对照Sprague-Dawley大鼠从妊娠第12天至第18天用多西环素（口服30 mg/kg体重）治疗。使用微标记造影剂评估胎盘灌注。在妊娠第18天对动物实施安乐死;获取生物统计数据，并分析滋养层侵袭。强力霉素导致两组胎儿宫内发育迟缓和较轻的胎盘。母体体重未受影响。如前所述，先兆子痫大鼠表现出更深的血管内滋养层浸润。然而，强力霉素治疗减少了先兆子痫大鼠滋养层的侵袭。生理性螺旋动脉重塑，如通过螺旋动脉轮廓中纤维蛋白样和肌动蛋白的沉积所评估的，被强力霉素显著降低。通过胎盘灌注测量评估的血管指数，在先兆子痫大鼠中用多西环素治疗后降低。因此，用强力霉素抑制基质金属蛋白酶导致滋养层侵袭减少和相关的胎盘灌注减少。这些研究首次表明，减少滋养层细胞诱导的血管重塑减少随后的胎盘灌注。我们的模型允许在体内研究失调的滋养层细胞侵袭和血管重塑，以获得对先兆子痫相关机制的重要见解。
Rats harboring the human angiotensinogen and human renin genes develop preeclamptic features in pregnancy. The preeclamptic rats exhibit a deeper trophoblast invasion associated with a reduced resistance index by uterine Doppler. Doxycycline inhibits matrix metalloproteinase activity. We tested the hypothesis that matrix metalloproteinase inhibition reduces trophoblast invasion with subsequent changes in placental perfusion. Preeclamptic and pregnant control Sprague-Dawley rats were treated with doxycycline (30 mg/kg of body weight orally) from gestational day 12 until day 18. Placental perfusion was assessed using a micromarker contrast agent. The animals were euthanized on day 18 of pregnancy; biometric data were acquired, and trophoblast invasion was analyzed. Doxycycline resulted in intrauterine growth retardation and lighter placentas in both groups. Maternal body weight was not affected. As shown earlier, preeclamptic rats exhibited a deeper endovascular trophoblast invasion. However, doxycycline treatment reduced trophoblast invasion in the preeclamptic rats. The physiological spiral artery remodeling, as assessed by the deposition of fibrinoid and -actin in the spiral artery contour, was significantly reduced by doxycycline. The vascularity index, as assessed by perfusion measurement of the placenta, was reduced after doxycycline treatment in preeclamptic rats. Thus, matrix metalloproteinase inhibition with doxycycline leads to reduced trophoblast invasion and associated reduced placental perfusion. These studies are the first to show that reducing trophoblast-induced vascular remodeling decreases subsequent placental perfusion. Our model allows the study of dysregulated trophoblast invasion and vascular remodeling in vivo to gain important insights into preeclampsia-related mechanisms.