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Vascular endothelial dysfunction is an early event in the development of atherosclerosis. Flow-mediated dilation (FMD) can be used to identify such endothelial dysfunction which is characterized by a decrease of nitric oxide (NO). Indeed, in subjects with coronary artery disease (CAD), microvascular FMD switches from a NO-mediated to a H 2 O 2 -mediated mechanism with corresponding elevations in mitochondrial reactive oxygen species (ROS). Recent evidence has shown an increase circulating mitochondrial DNA Damage-Associated Molecular Patterns ( mt DAMPs) in Coronary Heart Disease subjects and has been linked to vascular dysfunction. mt DAMPs signaling can activate the inflammatory response directly through activation of Toll Like Receptors 9 (TLR9). The effect of mt DAMPs on the endothelial function in the human microcirculation and the potential role for TLR9- mtDNA signaling axis to affect microvascular FMD, is unknown. In this study, we hypothesized that increased levels of mt DAMPs result in changes in microvascular redox environment that promote a loss of NO mediated dilation and elevation in mitochondrial derived ROS The incubation of cultured endothelial cells (ECs) with mt DAMPs decreased the ratio peNOS:teNOS in a time-dependent manner supporting the idea that mt DAMPs reduce NO bioavailability. This effect was eliminated when the ECs were pre-incubated with TLR9-targeted si-RNA. Prolonged (15-20H) ex vivo exposure to low dose of mt DAMPs (1ug/mL) changed the mechanism of FMD from NO to compensatory increase in H 2 O 2 to preserve overall dilator capacity in non-CAD human adipose micro-arterioles (% Max Diameter: Control 84.7±8.2; + L-NAME: 89.4±5.5; + Peg-Cat 35.4±10.8*; N=5, *pmt DAMPs (2.5ug/mL), the magnitude of the FMD was however significantly altered (% Max Diameter: high dose: 42.8 ±9.1* vs. low dose of mt DAMPs 84.7±8.2; N=4; p Our data suggest a potential pathogenic role of mt DAMPs in microvascular function through TLR9 to reduce NO bioavailability and induce endothelial dysfunction.

> “ But I think it [the Model] is more likely to change when, and because, far-reaching changes in the mental temper of our descendants demand that it should. The new Model will not be set up without evidence, but the evidence will turn up when the need for it becomes sufficiently great .” (222–223) The fate of biomedical research lies in the hands of future generations of scientists. In recent decades, the diversity of scientific career opportunities has exploded multidimensionally. However, the educational system for maintaining a pipeline of talented biomedical trainees remains unidimensional and has become outdated. This Viewpoint identifies inadequacies in training and offers potential solutions and implementation strategies to stimulate interest in science at a younger age and to better align individualized training pathways with career opportunities (precision training). Both interventions support of the ultimate goal of attracting the best possible future leaders in biomedical science . In his final published work, the eminent scholar C.S. Lewis describes the medieval model that dominated European intellectual life for centuries and explores how and why this model was replaced—because of discovery of dying stars, development of new scientific theories, and more. Aside from being a testament to an exceptional mind, C.S. Lewis’ The Discarded Image also contains wisdom directly relevant to the scientific milieu of the 21st century. Over the past 100 years, science and society have experienced unprecedented, dramatic change as a result of globalization, the Internet, advances in scientific capability, and an increasingly diverse and expanding scientific workforce. Such a large shift in the fabric of society has necessitated a corresponding shift in the environment in which we as scientists operate. However, scientific education lingers behind, using principles and processes that have not changed for many decades. The educational system responsible for training a new generation of …

The microcirculation is responsible for orchestrating adjustments in vascular tone to match local tissue perfusion with oxygen demand. Beyond this metabolic dilation, the microvasculature plays a critical role in modulating vascular tone by endothelial release of an unusually diverse family of compounds including nitric oxide, other reactive oxygen species, and arachidonic acid metabolites. Animal models have provided excellent insight into mechanisms of vasoregulation in health and disease. However, there are unique aspects of the human microcirculation that serve as the focus of this review. The concept is put forth that vasculoparenchymal communication is multimodal, with vascular release of nitric oxide eliciting dilation and preserving normal parenchymal function by inhibiting inflammation and proliferation. Likewise, in disease or stress, endothelial release of reactive oxygen species mediates both dilation and parenchymal inflammation leading to cellular dysfunction, thrombosis, and fibrosis. Some pathways responsible for this stress-induced shift in mediator of vasodilation are proposed. This paradigm may help explain why microvascular dysfunction is such a powerful predictor of cardiovascular events and help identify new approaches to treatment and prevention.