Carbon Monoxide Releasing Molecules Blunt Placental Ischemia-Induced Hypertension.

Abstract

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.