Role for Hydrogen Peroxide in Flow-Induced Dilation of Human Coronary Arterioles

Abstract

Abstract-Flow-induced dilation (FID) is dependent largely on hyperpolarization of vascular smooth muscle cells (VSMCs) in human coronary arterioles (HCA) from patients with coronary disease. Animal studies show that shear stress induces endothelial generation of hydrogen peroxide (H 2 O 2 ), which is proposed as an endothelium-derived hyperpolarizing factor (EDHF). We tested the hypothesis that H 2 O 2 contributes to FID in HCA. Arterioles (135Ϯ7 m, nϭ71) were dissected from human right atrial appendages at the time of cardiac surgery and cannulated with glass micropipettes. Changes in internal diameter and membrane potential of VSMCs to shear stress, H 2 O 2 , or to papaverine were recorded with videomicroscopy. In some vessels, endothelial H 2 O 2 generation to shear stress was monitored directly using confocal microscopy with 2Ј,7Ј-dichlorofluorescin diacetate (DCFH) or using electron microscopy with cerium chloride. Catalase inhibited FID (%max dilation; 66Ϯ8 versus 25Ϯ7%; PϽ0.05, nϭ6), whereas dilation to papaverine was unchanged. Shear stress immediately increased DCFH fluorescence in the endothelial cell layer, whereas treatment with catalase abolished the increase in fluorescence. Electron microscopy with cerium chloride revealed shear stress-induced increase in cerium deposition in intimal area surrounding endothelial cells. Exogenous H 2 O 2 dilated (%max dilation; 97Ϯ1%, ED 50 ; 3.0Ϯ0.7ϫ10 Ϫ5 mol/L) and hyperpolarized HCA. Dilation to H 2 O 2 was reduced by catalase, 40 mmol/L KCl, or charybdotoxin plus apamin, whereas endothelial denudation, deferoxamine, 1H-1,2,4 -oxadiazole-[4,3-a]quinoxalin-1-one, or glibenclamide had no effect. These data provide evidence that shear stress induces endothelial release of H 2 O 2 and are consistent with the idea that H 2 O 2 is an EDHF that contributes to FID in HCA from patients with heart disease. The full text of this article is available at http://www.circresaha.org. (Circ Res. 2003;92:e31-e40.)Key Words: human Ⅲ coronary microcirculation Ⅲ flow-induced dilation Ⅲ hydrogen peroxides P hysiologically, shear stress plays a critical role in the regulation of vascular tonus and vascular homeostasis, contributing to the maintenance of tissue perfusion and vascular integrity. Shear stress-induced release of nitric oxide (NO) from endothelial cells is widely recognized as one of the most important and common mechanisms for shear-induced vasomotion. For example, flow-induced release of NO is responsible for the mediation of flow-induced vasodilation (FID). [1][2][3] Animal studies have reported that the contribution of NO to FID is reduced as oxidative stress increases in the presence of risk factors for cardiovascular disease such as hypercholesterolemia 4 and hypertension. 5 In humans, in vivo and in vitro studies have demonstrated that relaxant factor(s) other than NO compensate to maintain FID when NO availability is reduced. 6,7 We recently reported that FID is mediated largely by endothelium-derived hyperpolarizing factor (EDHF) in human coronary arterioles (HCAs...

Beneficial effects of lifelong caloric restriction on endothelial function are greater in conduit arteries compared to cerebral resistance arteries

“…Similar to previous studies, we find that scavenging superoxide improves EDD in conduit and cerebral arteries from old mice (Blackwell et al 2004;Lesniewski et al 2009;Mayhan et al 2008;Modrick et al 2009) and does not affect EDD in conduit arteries from young or old CR mice (Csiszar et al 2009). However, we demonstrate that scavenging superoxide in the MCA from young and old CR mice results in reduced EDD, which is in accordance with previous studies demonstrating reactive oxygen species contribute to the dilation of resistance arteries in skeletal muscle (Sindler et al 2013;Trott et al 2011), cardiac muscle (Miura et al 2003;Feng et al 2010;Kang et al 2011), and cerebral tissue (Drouin et al 2007). Similarly, brachial artery dilation to handgrip exercise in humans, which is NO-dependent (Wray et al 2011), is improved in older adults following ingestion of an antioxidant cocktail, but is reduced in young adults after the same antioxidant cocktail .…”

NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

“…For example, whereas Nox1‐ and Nox2‐derived ${\mathrm{O}}_2^{-}$ regulate proinflammatory and mitogenic signaling pathways,37, 38 Nox4 generates mainly H 2 O 2 , an endothelium‐derived hyperpolarizing factor that controls vasodilation 39. The importance of NADPH oxidase‐derived ROS in the regulation of vascular tone was demonstrated in patients with hereditary deficiency of Nox2, who exhibit increased flow‐mediated vasodilation 40.…”

Arachidonic Acid Epoxygenase Metabolites Stimulate Endothelial Cell Growth and Angiogenesis via Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase/Akt Signaling Pathways

“…EETs activate vascular smooth muscle cell large conductance Ca 2ϩ -activated K ϩ channels leading to hyperpolarization of the resting membrane potential and resulting in vasorelaxation and lowering of blood pressure. Indeed, 11,12-EET has been proposed to be identical to endothelium-derived hyperpolarizing factor (Bauersachs et al, 1997;Bolz et al, 2000;Matoba et al, 2000Matoba et al, , 2002Hamilton et al, 2001;Lacza et al, 2002;Miura et al, 2003;Morikawa et al, 2003;Tanaka et al, 2003;Yada et al, 2003). Exogenous application of EETs inhibits vascular smooth muscle cell migration, platelet aggregation, nuclear factor-B activation, and vascular cell adhesion molecule-1 expression (Node et al, 1999;Fleming et al, 2001;Sun et al, 2002;Krotz et al, 2004), suggesting an overall beneficial role for EETs within the vasculature and a protective role in the development of atherosclerosis.…”