Gamma-Aminobutyric Acid is Synthesized by Endothelial Cells: Implications in Preeclampsia

摘要

Abstract Preeclampsia affects 3 to 6 % of pregnant women with devastating effects on the mother and the baby. However, there are no molecular targets that could drive drug discovery towards therapeutic success or early diagnostic markers that could predict the onset of this syndrome prior to development of symptoms. We have for the first time observed that gamma Aminobutyric acid (GABA) a central inhibitory neurotransmitter is synthesized and released by vascular endothelial cells into the systemic circulation and our findings therefore explain one important source of GABA in the systemic circulation. Furthermore, the level of GABA in the circulation is decreased in preeclampsia compared to non-pregnant women but the mechanism(s) involved is not known. The actions of GABA in the endothelial cells, and how a decrease in synthesis and release of GABA occurs in preeclampsia and its significance in the etiology of preeclampsia is not known. In preliminary experiments, we observed that human umbilical venous endothelial cells (HUVEC) obtained from pre- eclamptic pregnancies synthesize and release less GABA when compared with HUVEC obtained from normal pregnant women. We have also identified L-methionyl glutamate (LMG) in preeclamptic HUVEC which inhibits GABA synthesis by endothelial cells. Based on our novel observations, we HYPOTHESIZE that: “a decrease in endothelial synthesis and release of GABA is responsible for endothelial dysfunction and contributes to the pathogenesis of pre- eclampsia” and our hypothesis will be tested by the following three specific aims. Specific Aim 1: We will assess whether HUVEC obtained from mothers with pre-eclampsia (PE-HUVEC) synthesize and release less GABA when compared to those obtained from mothers with normal pregnancy. Specific Aim 2: We will compare the role of GABA in maintaining the normal functions of HUVEC obtained from normal pregnancies with relation to free fatty acid (FFA) oxidation, pyruvate oxidation, ATP synthesis, regulation of adhesion molecules expression and reactive oxygen species (ROS) generation and how decreased synthesis of GABA in PE-HUVEC affects these processes to cause endothelial cell dysfunction. Specific Aim 3: (a) We will assess the effects of the endogenous GABA synthesis inhibitor LMG, which is high in PE-HUVEC, on some of the GABA mediated functions of NP-HUVEC and HAEC as assessed under specific aim 2 and (b) we will quantify the levels of GABA and LMG in the cord and maternal blood of normal pregnancy and correlate this with the cord and maternal levels in preeclamptic pregnancy.