Severe trauma can overwhelm our endogenous hemostatic systems, and cause refractory coagulopathy and inflammation with potentially dire consequences. Paradoxically, regular exercise, which is perceived as improving our defenses against trauma, increases microscopic internal injury and thereby byproducts of cellular damage, such as histones, suggesting a counterintuitive protective or adaptive function of microscopic internal injuries. This concept has the potential to completely remold our view of the vascular response to trauma and can provide insights into new therapeutic targets. Our lack of understanding of how vascular endothelial cells (ECs), which line all blood vessels, sense the spectrum of trauma, and translate the signals of trauma into changes in vascular and immune functions, represents a significant void—but also an opportunity for clinical intervention. Our overall hypothesis is that histone-induced endothelial Ca2+ signaling is the translator of trauma to vascular functions. We will initially focus on two Ca2+ influx pathways, the polymodal transient receptor potential vanilloid 4 (TRPV4) ion channel, and the ionotropic purinergic receptor P2X7. In Aim 1, we explore the nature of EC Ca2+ signals, based on our novel data, which suggests that physiological levels of histones engage TRPV4 channels, and trauma levels activate P2X7 to induce Ca2+ entry. In Aim 2, we explore the functional consequences of histone-induced Ca2+ signaling on vascular responses, and test potential strategies to protect blood vessels from endothelial dysfunction after trauma. The proposed research project is expected to significantly advance the continuum of research needed to improve clinical outcomes in trauma. Moreover, it has the potential to radically change our view of endothelial cell biology, providing an enduring and sustained impact on our broader understanding of small vessels in health and disease.