Departments of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Am J Hypertens. 2017 Sep 1;30(9):931-937. doi: 10.1093/ajh/hpx070.
Preeclampsia is a pregnancy complication which manifests as new-onset hypertension, proteinuria, and a spectrum of other symptoms. While the underlying causes are still a subject of much debate, it is commonly believed that placental ischemia is a central cause. The ischemic placenta secretes factors which are believed to be responsible for the maternal syndrome; most notably the anti-angiogenic protein soluble fms-like tyrosine kinase 1 (sFlt-1). We have reported that induction of the carbon monoxide (CO) producing protein heme oxygenase-1 restored angiogenic imbalance and reduced blood pressure in a rat model of placental ischemia, and that CO blocks hypoxia-induced sFlt-1 production from placental tissue in vitro. We therefore hypothesized that direct administration of CO by a CO-releasing molecule (CORM) would blunt the placental ischemia-induced increase in sFlt-1 and thus the hypertension characteristic of this model.
We administered a soluble CO donor molecule (CORM-3) daily i.v. in control animals or those undergoing placental ischemia from GD14. Blood pressure and renal function were measured on GD19, and angiogenic markers measured by ELISA.
Interestingly, though we found that CORM administration significantly blunted the hypertensive response to placental ischemia, there was no concomitant normalization of sFlt-1 in either the placenta or maternal circulation. We did find, however, that CORM administration caused a significant increase in glomerular filtration rate, presumably by vasodilation of the renal arteries and increased renal plasma flow.
All in all these data suggest that administration of CO by CORMs do lower blood pressure during placental ischemia mechanisms independent of changes in angiogenic balance.
子痫前期是一种妊娠并发症，表现为新发生的高血压、蛋白尿和一系列其他症状。虽然其根本原因仍存在很大争议，但普遍认为胎盘缺血是一个核心原因。缺血的胎盘会分泌一些因子，这些因子被认为是导致母体综合征的原因；其中最明显的是抗血管生成蛋白可溶性 fms 样酪氨酸激酶 1（sFlt-1）。我们曾报道，诱导一氧化碳（CO）产生蛋白血红素加氧酶-1（HO-1）可恢复血管生成失衡并降低胎盘缺血大鼠模型的血压，并且 CO 可阻断体外胎盘组织缺氧诱导的 sFlt-1 产生。因此，我们假设通过 CO 释放分子（CORM）直接给予 CO 会抑制胎盘缺血引起的 sFlt-1 增加，从而减轻该模型的高血压特征。
我们在对照组或从 GD14 开始发生胎盘缺血的动物中每天静脉内给予可溶性 CO 供体分子（CORM-3）。在 GD19 测量血压和肾功能，并通过 ELISA 测量血管生成标志物。
有趣的是，尽管我们发现 CORM 给药显著抑制了胎盘缺血引起的高血压反应，但胎盘或母体循环中的 sFlt-1 并没有同时正常化。然而，我们确实发现 CORM 给药导致肾小球滤过率显著增加，推测是通过肾动脉扩张和增加肾血浆流量。
总之，这些数据表明，CORM 给药通过独立于血管生成平衡变化的机制在胎盘缺血期间降低血压。
