title: Transition in the mechanism of flow-mediated dilation with aging and development of coronary artery disease.
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 H2O2was 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 H2O2emerges 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.
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, USA. abeyer@mcw.edu.|Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, HRC H4875, 8701 Watertown Plank Rd., Milwaukee, WI, 53226, USA. abeyer@mcw.edu.
authors.forename: Andreas M
authors.identifier: 0000-0001-9129-7492
authors.initials: AM
authors.lastname: Beyer
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, USA.|Department of Health and Medicine, Carroll University, Waukesha, USA.
authors.forename: Natalya
authors.initials: N
authors.lastname: Zinkevich
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Miller
authors.affiliation: NIH NIGMS, Bethesda, USA.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, HRC H4875, 8701 Watertown Plank Rd., Milwaukee, WI, 53226, USA.
authors.forename: April L
authors.initials: AL
authors.lastname: Wittenburg
authors.affiliation: Children's Hospital of Wisconsin, Wauwatosa, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mitchell
authors.affiliation: Wheaton Franciscan Healthcare, Wheaton, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Galdieri
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Sorokin
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, USA.|Clement J. Zablocki VA Medical Center Milwaukee, Milwaukee, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Gutterman
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging / Q000473:pathology*; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D003324:Coronary Artery Disease / Q000503:physiopathology*; D003331:Coronary Vessels / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D017382:Reactive Oxygen Species; D014664:Vasodilation / Q000502:physiology*; D055815:Young Adult
chemical_list: D017382:Reactive Oxygen Species
keywords: Coronary artery disease; Flow-mediated dilation; Microvasculature; Vasodilation