From the Division of Vascular Medicine and Pharmacology, Department of Internal Medicine (K.V., L.S., S.L., J.E.I.S., M.M.v.I., I.M.G., E.C.H.F., A.H.v.d.M., A.H.J.D.), Division Obstetrics and Prenatal Medicine, Department of Obstetrics and Gynaecology (W.V.), and Department of Clinical Chemistry (H.R.), Erasmus MC, Rotterdam, The Netherlands.
Hypertension. 2015 Jun;65(6):1316-23. doi: 10.1161/HYPERTENSIONAHA.115.05267. Epub 2015 Apr 13.
Women with preeclampsia display low renin-angiotensin-aldosterone system activity and a high antiangiogenic state, the latter characterized by high levels of soluble Fms-like tyrosine kinase (sFlt)-1 and reduced placental growth factor levels. To investigate whether renin-angiotensin-aldosterone system suppression in preeclampsia is because of this disturbed angiogenic balance, we measured mean arterial pressure, creatinine, endothelin-1 (ET-1), and renin-angiotensin-aldosterone system components in pregnant women with a high (≥85; n=38) or low (<85; n=65) soluble Fms-like tyrosine kinase-1/placental growth factor ratio. Plasma ET-1 levels were increased in women with a high ratio, whereas their plasma renin activity and plasma concentrations of renin, angiotensinogen, and aldosterone were decreased. Plasma renin activity-aldosterone relationships were identical in both the groups. Multiple regression analysis revealed that plasma renin concentration correlated independently with mean arterial pressure and plasma ET-1. Plasma ET-1 correlated positively with soluble Fms-like tyrosine kinase-1 and negatively with plasma renin concentration, and urinary protein correlated with plasma ET-1 and mean arterial pressure. Despite the lower plasma levels of renin and angiotensinogen in the high-ratio group, their urinary levels of these components were elevated. Correction for albumin revealed that this was because of increased glomerular filtration. Subcutaneous arteries obtained from patients with preeclampsia displayed an enhanced, AT2 receptor-mediated response to angiotensin II. In conclusion, a high antiangiogenic state associates with ET-1 activation, which together with the increased mean arterial pressure may underlie the parallel reductions in renin and aldosterone in preeclampsia. Because ET-1 also was a major determinant of urinary protein, our data reveal a key role for ET-1 in the pathogenesis of preeclampsia. Finally, the enhanced angiotensin responsiveness in preeclampsia involves constrictor AT2 receptors.
患有先兆子痫的女性表现出低肾素-血管紧张素-醛固酮系统活性和高抗血管生成状态，后者的特征是可溶性 Fms 样酪氨酸激酶 1（sFlt-1）水平升高和胎盘生长因子水平降低。为了研究先兆子痫中肾素-血管紧张素-醛固酮系统抑制是否是由于这种血管生成平衡紊乱引起的，我们测量了高（≥85；n=38）或低（<85；n=65）可溶性 Fms 样酪氨酸激酶 1/胎盘生长因子比值的孕妇的平均动脉压、肌酐、内皮素-1（ET-1）和肾素-血管紧张素-醛固酮系统成分。高比值组的女性血浆 ET-1 水平升高，而其血浆肾素活性和血浆肾素、血管紧张素原和醛固酮浓度降低。两组的血浆肾素活性-醛固酮关系相同。多元回归分析显示，血浆肾素浓度与平均动脉压和血浆 ET-1 独立相关。血浆 ET-1 与可溶性 Fms 样酪氨酸激酶 1 呈正相关，与血浆肾素浓度呈负相关，尿蛋白与血浆 ET-1 和平均动脉压呈正相关。尽管高比值组的血浆肾素和血管紧张素原水平较低，但它们的尿中这些成分的水平升高。白蛋白校正表明，这是由于肾小球滤过增加。从先兆子痫患者获得的皮下动脉显示对血管紧张素 II 的增强、AT2 受体介导的反应。总之，高抗血管生成状态与 ET-1 激活相关，这与平均动脉压升高一起可能是先兆子痫中肾素和醛固酮平行减少的基础。由于 ET-1 也是尿蛋白的主要决定因素，我们的数据揭示了 ET-1 在先兆子痫发病机制中的关键作用。最后，先兆子痫中增强的血管紧张素反应涉及收缩性 AT2 受体。
