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Transition in the mechanism of flow-mediated dilation with aging and development of coronary artery disease

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Abstract

In microvessels of patients with coronary artery disease (CAD), flow-mediated dilation (FMD) is largely dependent upon the endothelium-derived hyperpolarizing factor H2O2. The goal of this study is to examine the influence of age and presence or absence of disease on the mechanism of FMD. Human coronary or adipose arterioles (~150 µm diameter) were prepared for videomicroscopy. The effect of inhibiting COX [indomethacin (Indo) or NOS (L-NAME), eliminating H2O2 (polyethylene glycol-catalase (PEG-CAT)] or targeting a reduction in mitochondrial ROS with scavengers/inhibitors [Vitamin E (mtVitamin E); phenylboronic acid (mtPBA)] was determined in children aged 0–18 years; young adults 19–55 years; older adults >55 years without CAD, and similarly aged adults with CAD. Indo eliminated FMD in children and reduced FMD in younger adults. This response was mediated mainly by PGI2, as the prostacyclin-synthase-inhibitor trans-2-phenyl cyclopropylamine reduced FMD in children and young adults. L-NAME attenuated dilation in children and younger adults and eliminated FMD in older adults without CAD, but had no effect on vessels from those with CAD, where mitochondria-derived H2O2 was the primary mediator. The magnitude of dilation was reduced in older compared to younger adults independent of CAD. Exogenous treatment with a sub-dilator dose of NO blocked FMD in vessels from subjects with CAD, while prolonged inhibition of NOS in young adults resulted in a phenotype similar to that observed in disease. The mediator of coronary arteriolar FMD evolves throughout life from prostacyclin in youth, to NO in adulthood. With the onset of CAD, NO-inhibitable release of H2O2 emerges as the exclusive mediator of FMD. These findings have implications for use of pharmacological agents, such as nonsteroidal anti-inflammatory agents in children and the role of microvascular endothelium in cardiovascular health.

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Abbreviations

BMI:

Body mass index

BSA:

Bovine serum albumin

CAD:

Coronary artery disease

COX:

Cyclooxygenase

eNOS:

Endothelial nitric oxide synthase

FMD:

Flow-mediated dilation

H2O2 :

Hydrogen peroxide

L-NAME:

NG-Nitro-l-arginine methyl ester

mt:

Mitochondrial

MitoPY1:

Mitochondria peroxy yellow 1

NO:

Nitric oxide

PBA:

Phenylboronate

PGI2 :

Prostacyclin

ROS:

Reactive oxygen species

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Acknowledgements

We thank the surgeons and nurses at Froedtert Hospital, the Division of Cardiothoracic Surgery at the Medical College of Wisconsin, the Cardiothoracic Surgery Division at the Zablocki Veterans Affairs Medical Center in Milwaukee, the Children’s Hospital of Wisconsin, the Aurora Medical Group Cardiovascular and Thoracic Surgery, Cardiothoracic Surgery Group of Milwaukee, the Wheaton Hospital Group including St. Joseph’s, The Wisconsin Heart Hospital, Elmbrook Memorial of Brookfield, and The Wisconsin Donor Network for providing tissue.

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Authors and Affiliations

  1. Department of Medicine, Medical College of Wisconsin, Milwaukee, USA

    Andreas M. Beyer, Natalya Zinkevich, Bradley Miller, Andrey Sorokin & David D. Gutterman

  2. Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, HRC H4875, 8701 Watertown Plank Rd., Milwaukee, WI, 53226, USA

    Andreas M. Beyer & April L. Wittenburg

  3. Department of Health and Medicine, Carroll University, Waukesha, USA

    Natalya Zinkevich

  4. NIH NIGMS, Bethesda, USA

    Yanping Liu

  5. Children’s Hospital of Wisconsin, Wauwatosa, USA

    Michael Mitchell

  6. Wheaton Franciscan Healthcare, Wheaton, USA

    Ralph Galdieri

  7. Clement J. Zablocki VA Medical Center Milwaukee, Milwaukee, USA

    David D. Gutterman

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  1. Andreas M. Beyer
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Correspondence to Andreas M. Beyer.

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Funding

This work was supported by National Institutes of Health Grants R01-HL-113612 (to D. D. Gutterman), R21-OD-018306 (to A. M. Beyer). We received support from the Clinical and Translational Science Award (CTSA) program of NCATS for writing assistance (Glenn Krakower Grant 8UL1TR000055).

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Beyer, A.M., Zinkevich, N., Miller, B. et al. Transition in the mechanism of flow-mediated dilation with aging and development of coronary artery disease. Basic Res Cardiol 112, 5 (2017). https://doi.org/10.1007/s00395-016-0594-x

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