The Role of Marinobufagenin in the Causation of a Cerebral Vascular Leak Syndrome in a Rat Model of Human Preeclampsia

Preeclampsia (PE) is a hypertensive disorder of pregnancy, in which marinobufagenin (MBG) is elevated. Cerebral edema represents a breach of the blood‐brain barrier (BBB) and is a potential complication of PE. We investigated alterations in the endothelial cells of the cerebral circulation in rats rendered “PE” as well as the effect of MBG on these alterations. The BBB permeability was assessed in PE and control pregnant rats by extravasation of Evan's blue dye into brain parenchyma. Human brain microvascular endothelial cells were utilized to examine alterations in monolayer permeability and the change in phosphorylation of MAPK caused by MBG. Apoptosis was evaluated by examining alterations in caspases and annexin‐V staining and endothelial tight junction proteins were determined by immunofluorescence. In the striatum, the extent of dye extravasation was greater in PE rats than in controls. Concentrations of MBG ≥1 nM induced an increase in monolayer permeability, caused a significant decrease in the phosphorylation of ERK1/2 and activated the phosphorylation of Jnk, p38, and Src. It also significantly increased the apoptotic signaling, which was prevented by a p38 inhibitor. Additionally, MBG caused the disruption of endothelial adherens tight junction proteins. These data provide evidence that in human PE, MBG may play an important role in the neurologic abnormalities often seen in that syndrome.