(120b) Quantification of Metabolic Differences in Platelets Exposed to Estrogen Using Flux Balance Analysis

Platelets, while essential to human health, are implicated in severe health problems such as heart attacks, strokes, and venous thrombosis. Pre-menopausal women have lower incidences of these events compared to post-menopausal women and men, leading to a hypothesis that estrogen has a cardioprotective effect (Maccarrone et al 2015, Khetawat et al 2000). However, it has also been observed that women on hormonal oral contraceptives are at an increased risk (4-6 fold) of venous thrombosis (Vinogradova et al 2015). Conflicting studies exist on the effect of estrogen on platelets both in vivo and ex vivo (Grodstein et al 2000, Cushman et al 2004, Bar et al 2000, Moro et al 2005). Here, we apply metabolomic and fluxomic techniques to quantify changes in resting platelet metabolism upon acute exposure to physiologically relevant concentrations of estrogen with reaction level resolution. 124 extracellular metabolites and 175 intracellular metabolites were analyzed over 180 minutes for platelets exposed to 10 nM estradiol, 100 nM estradiol, or vehicle control. These experimental measurements were used to constrain a flux balance analysis model to identify differences in key energy and activation pathways: central carbon metabolism and arachidonic acid metabolism. Quantifying changes in resting metabolism upon estrogen treatment may help explain differences in activation between estrogen treated/untreated platelets, as well as explain sexual dimorphisms in platelet behavior in vivo.

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