Physiological Consequences of Coronary Arteriolar Dysfunction and Its Influence on Cardiovascular Disease: Diagnostic and Additional Therapeutic Consequences.

Abstract

TO THE EDITOR: In Physiology, we read with interest the review article by Allaqaband et al. (1) stressing the contribution of coronary microvascular dysfunction to coronary artery disease (CAD) and thus the need for novel arteriole-specific therapeutic approaches. The authors are congratulated for the crisp summary of their pioneering works indicating that, in coronary arterioles of CAD patients, endothelial release of nitric oxide (NO) is shifted to hydrogen peroxide (H2O2). The cardiovascular research community is increasingly aware of the important contributions of microvascular dysfunction to cardiac (1) and neurodegenerative diseases (4). Here, we formulate diagnostic and additional potential therapeutic consequences of the subject reviewed by the Milwaukee group. The experiments summarized by Allaqaband et al. (1) showed that the transition of endothelium-derived NO to H2O2 can be observed in not only coronary but also adipose tissue arterioles of CAD patients. This suggests that it might be monitored noninvasively in the periphery with predictive value for the coronary circulation. Various established and novel non-invasive approaches of the human microcirculation and human resistance artery function are available to accomplish this (7). They include venous occlusion plethysmography, nailfold capillaroscopy, retinoscopy (22), dynamic optical coherence tomography (2, 20, 21), and label-free photoacoustic imaging (16, 17). Demonstration of endothelium-derived H2O2 in isolated arterioles in vitro involves 1) resistance to treatment with an inhibitor of NO synthase, 2) inhibition by catalase (scavenger of H2O2), and 3) increased fluorescence of a H2O2-selective probe, which cannot all be used in the intact human in vivo. In theory, ebselen [alternative scavenger of H2O2 used in human research (23)] and the use of two-photon microscopy on the skin [reviewed by Guo et al. (10)] may fill these gaps in the future. Still, the experimental evidence summarized by Allaqaband et al. (1) invites consideration of two forms of dysfunction of endothelium-dependent vasodilatation: quantitative and qualitative endothelial dysfunction. In the former, the amplitude of the vasodilator response to an endothelium-dependent stimulus is reduced. In the latter, the magnitude of the endothelium-dependent vasodilatation is maintained but no longer mediated by NO {i.e., resistant to inhibitors of NO synthase but blocked by tetraethyl ammonium [inhibitor of endothelium-dependent hyperpolarization in the human forearm (11)] and possibly by catalase or ebselen}. Determining whether the latter is a dysfunction or a compensation will require monitoring of the damage done by endothelium-derived H2O2. In contrast to the protein changes induced by peroxynitrite (ONOO, the product of NO and superoxide anion) (19), there is no consensus on fingerprints of H2O2-induced vascular damage (8). Guidelines have been proposed to facilitate high-quality measurements of both reactive oxygen species and reactive nitrogen species (9), yet identification of markers at all levels (from laboratory research to clinic) of specific H2O2-induced damage is missing. This would be highly relevant to not only coronary microvascular dysfunction but also to cerebrovascular causes of neurodegeneration (4). Most of the experimental evidence reviewed by Allaqaband et al. (1) was obtained in isolated coronary and adipose tissue arterioles from patients with and without CAD who were constricted with endothelin-1 in vitro. We reported (14, 15) that the relaxing responses of pericardial resistance arteries from patients requiring cardio-thoracic surgery ( 70% with CAD) to the endothelium-dependent vasodilator bradykinin are 1) blocked by an inhibitor of NO synthase during contraction induced by depolarization or by a thromboxane A2 mimetic and 2) are blocked by catalase, but not inhibitor of NO-synthase, during contraction induced by endothelin-1. This may put endothelin-1 in the center of the transition of endothelium-derived NO to H2O2 advocated in the elegant review by Allaqaband et al. (1). It also adds inhibitors of endothelin-converting enzyme, inhibitors of multiple metalloproteases (13, 18), and antagonists of endothelin receptors (5) to the arteriole-specific therapeutic considerations elaborated by Allaqaband et al. (1). A shift of endothelium-derived NO to H2O2 may not be the end of the line. In coronary arterioles and pericardial resistance arteries from CAD patients, a statistically significant vasodilatation in response to bradykinin persists when NO synthase is inhibited and H2O2 is scavenged (12, 14). In the coronary vessels, this could be attributed to unmasking of endothelium-derived epoxyeicosatrienoic acid produced from arachidonic acid by endothelial cytochrome P450 and activating smooth muscle large conductance calcium-activated K channels (12). Cytochrome P450 is inhibited by NO (3) and by H2O2 (12), but can be activated when the bioavailability of the radicals is reduced. In 2016, these interactions were among others reviewed by Ellinsworth et al. (6). A final word of caution is that properties of arterioles isolated from CAD patients can result from the risk factors that contributed to the development of large coronary artery disease, from the consequences of CAD, and from the various drugs that CAD patients are treated with before they are referred to coronary artery bypass surgery. It is of note, in this respect, that the vessels from these patients exhibit substantial endothelium-dependent vasodilator responses to bradykinin and increased shear stress (1, 14). The potency and efficacy of these endothelium-dependent stimuli is similar in these vessels compared with those reported for arterioles and resistance arteries from individuals without CAD or its extensive chronic drug treatment. The endotheliLETTER TO THE EDITOR Jo G. R. De Mey, Maria Bloksgaard and Christian Aalkjær2 University of Southern Denmark, Odense, Denmark; and Aarhus University, Aarhus, Denmark PHYSIOLOGY 34: 82–83, 2019.