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 HO. 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 HO (polyethylene glycol-catalase (PEG-CAT)] or targeting a reduction in mitochondrial ROS with scavengers/inhibitors [Vitamin E (Vitamin E); phenylboronic acid (PBA)] 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 PGI, 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 HO 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 HO 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.

Contribution of mitochondria‐derived free radicals to endothelial dysfunction in human skeletal muscle feed arteries: another hazard of the ageing process

“…Based on those observations, the authors concluded that endothelium‐dependent dilation of microvessels was maintained after heavy resistance exercise in exercise‐trained individuals but not in sedentary subjects and that the mediator of endothelium‐dependent dilation of these vessels changes from NO prior to exercise to H 2 O 2 after heavy resistance exercise or exposure to high pressure alone. Finally, as noted in a recent review by Beyer et al ., the mechanisms of flow‐mediated dilation in human coronary arteries can change not only with age (from prostacyclin in youth to NO in adulthood) but also with coronary artery disease (H 2 O 2 ‐mediated). Taken together, the results of earlier studies and those of the present study by Park et al .…”

“…Finally, as noted in a recent review by Beyer et al ., the mechanisms of flow‐mediated dilation in human coronary arteries can change not only with age (from prostacyclin in youth to NO in adulthood) but also with coronary artery disease (H 2 O 2 ‐mediated). Taken together, the results of earlier studies and those of the present study by Park et al . highlight the complexities associated with age‐related impairment in vascular function and generate interesting questions about potential changes in the mediators and mechanisms of endothelium‐dependent dilation with age, disease and exercise training.…”

Lysophosphatidic acid acts on LPA1receptor to increase H2O2during flow‐induced dilation in human adipose arterioles

“…We extend these findings and demonstrate that acutely elevated levels of LPA disrupt endothelium‐dependent FID in human arterioles by shifting the mechanism away from NO to mtH 2 O 2 . There was a noticeable improvement in dilation at lower pressure gradients after L‐NAME treatment (Figure B), which could potentially be ascribed to elimination of uncoupled eNOS‐derived reactive nitrogen/oxygen species, which scavenge the dilatory ROS (Yang et al ., ) or the fact that quenching any remaining NO releases the block on mtH 2 O 2 (Beyer et al ., ). LPA significantly reduced dilation to ACH, potentially by increasing intracellular ROS, which can compromise endothelial NO bioavailability.…”

“…A.U.arbitrary units, (n) indicates number of subjects. (Beyer et al, 2017). LPA significantly reduced dilation to ACH, potentially by increasing intracellular ROS, which can compromise endothelial NO bioavailability.…”

David Gutterman

“…[1][2][3] In its primary role, TERT acts in the nucleus to maintain telomere length, stabilizing DNA. Gutterman and his colleague, Dr Andreas Beyer, found that TERT unexpectedly plays an additional role outside the nucleus.…”