994 MARINOBUFAGENIN CAUSES CEREBRAL VASCULAR LEAK SYNDROME IN PREECLAMPSIA

Abstract

Objective: Preeclampsia (PreE) is a hypertensive disease during pregnancy with multiple pathophysiologic triggers. We have shown that the urinary excretion of marinobufagenin (MBG) is elevated prior to the development of symptoms. Vasogenic cerebral edema is a potential PreE complication. We investigated the effects of MBG on cerebral circulation in “PreE” rats and the underlying mechanisms. Study Design: (1) MBG levels and angiogenic factors were assayed in the urine samples of 17 PreE and 23 NP patients. (2) Blood-brain barrier (BBB) permeability in normal pregnant (NP), “PreE” and MBG-infused pregnant (NPM) rats was assessed by Evan's blue dye extravasation. (3) Human brain microvascular endothelial cells (HBMEC) were used to test for effects of MBG on monolayer permeability and phosphorylation of ERK1/2, Jnk, p38, and Src. Apoptosis was evaluated by caspase 3/7 and annexin-V staining with and without pretreatment with p38 inhibitor. Effects of MBG on endothelial tight junction proteins were assessed. Results: (1) MBG levels were higher and angiogenic imbalance was observed in PreE patients compared to NP. (2) Dye extravasation was greater (p < 0.05) in “PreE” and NPM compared to NP rats. (3) Concentrations of MBG ≥ 1 nM significantly increased monolayer permeability, caused a significant decrease in ERK1/2 and activated Jnk, p38, and Src phosphorylation. The activation of apoptosis was prevented by pretreatment with a p38 inhibitor. MBG caused the disruption of endothelial adherens tight junction proteins. Conclusions: These data provide evidence for the view that MBG play an important role in cerebral edema and neurologic abnormalities seen in PreE.