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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL113612-02
Application #
8620712
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Charette, Marc F
Project Start
2013-02-15
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Durand, Matthew J; Zinkevich, Natalya S; Riedel, Michael et al. (2016) Vascular Actions of Angiotensin 1-7 in the Human Microcirculation: Novel Role for Telomerase. Arterioscler Thromb Vasc Biol 36:1254-62
Ellinsworth, David C; Sandow, Shaun L; Shukla, Nilima et al. (2016) Endothelium-Derived Hyperpolarization and Coronary Vasodilation: Diverse and Integrated Roles of Epoxyeicosatrienoic Acids, Hydrogen Peroxide, and Gap Junctions. Microcirculation 23:15-32
Kadlec, Andrew O; Chabowski, Dawid S; Ait-Aissa, Karima et al. (2016) Role of PGC-1α in Vascular Regulation: Implications for Atherosclerosis. Arterioscler Thromb Vasc Biol 36:1467-74
Nishijima, Yoshinori; Cao, Sheng; Chabowski, Dawid S et al. (2016) Contribution of KV1.5 Channel to H2O2-Induced Human Arteriolar Dilation and its Modulation by Coronary Artery Disease. Circ Res :
Gutterman, David D; Chabowski, Dawid S; Kadlec, Andrew O et al. (2016) The Human Microcirculation: Regulation of Flow and Beyond. Circ Res 118:157-72
Beyer, Andreas M; Freed, Julie K; Durand, Matthew J et al. (2016) Critical Role for Telomerase in the Mechanism of Flow-Mediated Dilation in the Human Microcirculation. Circ Res 118:856-66
Chabowski, Dawid; Gutterman, David (2015) Unveiling the Mechanism of Coronary Metabolic Vasodilation: Voltage-Gated Potassium Channels and Hydrogen Peroxide. Circ Res 117:589-91
Durand, Matthew J; Dharmashankar, Kodlipet; Bian, Jing-Tan et al. (2015) Acute exertion elicits a H2O2-dependent vasodilator mechanism in the microvasculature of exercise-trained but not sedentary adults. Hypertension 65:140-5
Beyer, Andreas M; Durand, Matthew J; Hockenberry, Joseph et al. (2014) An acute rise in intraluminal pressure shifts the mediator of flow-mediated dilation from nitric oxide to hydrogen peroxide in human arterioles. Am J Physiol Heart Circ Physiol 307:H1587-93
Durand, Matthew J; Gutterman, David D (2014) Exercise and vascular function: how much is too much? Can J Physiol Pharmacol 92:551-7

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