Vascular homeostasis is highly dependent upon factors released from the endothelium, the most prominent of which are nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). Each plays a role in shear- (or flow-)mediated dilation (FMD), the most important physiological endothelium-dependent dilator response. Aging or the presence of coronary disease (CAD) and its risk factors can change these mediators of dilation. Our preliminary data demonstrate for the first time in human hearts, that prostaglandins mediate FMD in children, while in adults without CAD, NO plays the predominant role. However in vessels from subjects with CAD, EDHF (hydrogen peroxide; H2O2) is the sole mediator of FMD in the coronary microcirculation. While this diversity in mediator release from the endothelium may be beneficial to maintain dilation, each mediator has a different biological effect on cellular proliferation, apoptosis, and propensity for atherosclerosis. Thus understanding which mediator is involved at different stages of life and how they change in the presence of disease is critical to a better understanding of vascular pathology including atherosclerosis. The overall goal of this application is to determine the pathways by which signaling plasticity ensures continued dilator responses to shear throughout life, and to understand the mechanism involved in the change from health to disease. We will explore the hypothesis that NO which mediates FMD in adults without CAD acts in parallel to suppress mitochondrial ROS. We will test the novel hypothesis that NO-activation of PGC-1 , which stimulates mitochondrial biogenesis and inhibits generation of reactive oxygen species, is responsible for this suppression. We will pursue the mechanism further by testing whether telomerase activity, critically linked to the aging process, also modulates signaling pathways activated by shear. It is proposed that telomerase is a key intermediary, activated by NO which in turn stimulates PGC-1. Decreased telomerase activity is expected to provoke a transition to endothelial derived H2O2 as a key mediator of FMD in disease. We will also explore provocative preliminary data showing that neutral sphingomyelinase-stimulated production of ceramide could orchestrate the transition from NO to H2O2 by elevating cellular ROS and reducing telomerase activity. The proposed work provides new translational and mechanistic insight into the effect of aging and disease on endothelial pathophysiology in the human heart with direct implications for the development and prevention of promontory vascular changes that lead to coronary artery disease.

Public Health Relevance

Coronary artery disease CAD, as the leading cause of death in both men and women often results from alterations in the microcirculation, however most studies of the coronary microcirculation have been done in animals and there is little understanding of changes in coronary vascular function over time and with disease in humans. We hypothesize that there is a change in mechanism of dilation in human coronary microvessels with age and with the onset CAD which could help explain the development of this disease process. The overall goal of this application is to determine the mechanism by which plasticity of vasodilator pathways ensures continued dilator responses to shear throughout life and to understand the mechanism involved in the change from health to disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Charette, Marc F
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Medical College of Wisconsin
Internal Medicine/Medicine
Schools of Medicine
United States
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Kadlec, Andrew O; Barnes, Chad; Durand, Matthew J et al. (2018) Microvascular Adaptations to Exercise: Protective Effect of PGC-1 Alpha. Am J Hypertens 31:240-246
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