Cardiovascular disease is the major cause of morbidity and mortality in the United States. While varied in clinical presentation, it is generally assumed that inflammation is a common mechanism of cardiovascular disease pathogenesis. The vascular endothelium is the structural lining of all blood vessels that serves as an active barrier between the circulation and the surrounding tissue. As such, endothelial cells (ECs) are increasingly recognized as a vital participant in the inflammatory signaling cascade. A common mechanism by which ECs sense inflammatory signals is by an increase in intracellular calcium (Ca2+) via the second messenger inositol 1,4,5-trisphosphate (InsP3), which binds to InsP3 receptors (InsP3Rs) on the endoplasmic reticulum. Despite their ubiquitous presence in the vasculature, ECs display a great degree of heterogeneity in the InsP3R -mediated Ca2+ response that is dependent upon the vascular origin of the endothelial culture. Unfortunately, how heterogenous Ca2+ signals are generated and how they impact endothelial function are unknown. The focus of my work has been to understand the delicate interaction between Ca2+ signals and mitochondrial function, and how this interaction impacts endothelial homeostasis. Recently, I have discovered that InsP3R -mediated Ca2+ transmits to the mitochondria, which 'decode' these Ca2+ signals into reactive oxygen species (ROS) and endothelial inflammation. Thus far, we have discovered that ROS may selectively modify InsP3Rs to mediate intracellular Ca2+ signaling. Persistent modifications in cellular ROS production alter calcium signaling further and lead to cellular dysfunction. The goal of this project is to investigate whether heterogeneous Ca2+ signaling is due to the selective modification of InsP3R type 1 and 2 in ECs by oxidants, how mitochondrial ROS impacts EC Ca2+ signaling, and ultimately, how these calcium signaling patterns trigger inflammatory signaling via the transcription factor NF-kB. While a correlative link between mitochondrial function, ROS production, and EC inflammation exists, a causative link between these variables has not been established. If a definitive link can be made, agents designed to counter specific InsP3R activity and mitochondrially-targeted antioxidant compounds may constitute an attractive therapeutic target during vascular inflammatory conditions.