The mechanism of flow-induced dilation in human adipose arterioles involves hydrogen peroxide during CAD

Abstract

Phillips SA, Hatoum OA, Gutterman DD. The mechanism of flowinduced dilation in human adipose arterioles involves hydrogen peroxide during CAD. Am J Physiol Heart Circ Physiol 292: H93-H100, 2007. First published October 13, 2006; doi:10.1152/ajpheart.00819.2006 is an important physiological stimulus that regulates tissue blood flow and is mediated by endotheliumderived factors that play a role in vascular integrity and the development of atherosclerosis. In coronary artery disease (CAD), conduit artery FID is impaired. The purpose of this study was to determine the mechanism of FID in human visceral adipose and examine whether the presence of conduit coronary atherosclerosis is associated with altered endothelial function in visceral fat. FID was determined in isolated visceral fat arterioles from patients with and without CAD. After constriction with endothelin-1, increases in flow produced an endothelium-dependent vasodilation that was sensitive to N -nitro-Larginine methyl ester (L-NAME) in visceral fat arterioles from patients without CAD. In contrast, L-NAME alone or in combination with indomethacin had no effect on FID in similarly located arterioles from patients with CAD. Flow increased dichlorofluorescein (DCF) and dihydroethidium fluorescence accumulation in arterioles from patients with CAD versus without, indicative of the production of oxidative metabolites and superoxide, respectively. Both the dilation and DCF fluorescence to flow were reduced in the presence of the H 2O2 scavenger polyethylene glycol-catalase. Exogenous H2O2 elicited similar relaxations of arterioles from patients in both groups. These data indicate that FID in visceral fat arterioles is nitric oxide dependent in the absence of known CAD. However, in the presence of CAD, H 2O2 replaces nitric oxide as the mediator of endotheliumdependent FID. This study provides evidence that adverse microvascular changes during CAD are evident in human visceral adipose, a tissue associated with CAD. coronary artery disease; blood flow; vasodilation; microcirculation FLOW-INDUCED DILATION (FID) is a physiologically important stimulus regulating vascular tone and homeostasis of the peripheral circulation. This important endothelial mechanism of vasodilation occurs in virtually every vascular bed and, in large arteries, may be critical for preventing atherosclerosis through release of the endothelium-derived antiproliferative compounds nitric oxide (NO) and prostacyclin (PGI 2 ) (21,25,39,51). Many of the studies implicating the role of NO (24) and PGI 2 (26) in FID have been performed in animal models in the absence of coronary artery disease (CAD). However, no studies have evaluated the mechanism of FID in isolated human microvessels from human visceral adipose with or without CAD. Human adipose has been proposed as a source for endocrine and paracrine modulation of vascular function during the establishment of atherosclerosis, and therefore vessels in this region could serve as sentinels for endothelial alterations produced by the proatheroscler...

Mitochondrial Ca 2+ transport in the endothelium: regulation by ions, redox signalling and mechanical forces

“…By contrast, eNOS expression was decreased under OS in vivo, compared with PS, and in vitro, compared with static controls (figure 3d) [153,155,156]. In agreement with that, isolated arterioles from animals/humans showed NO-dependent dilation under PS or SS; OS did not induce dilation [157,158]. PS (or SS) was found to trigger EC secretion of ATP causing autocrine/paracrine activation of surface purinergic receptors (G q /G 11 protein-coupled P2Y 2 Rs), activation of PLC, generation of IP 3 The pro-inflammatory signalling pathways underlying atherogenesis, including c-Jun N-terminal kinase (JNK)/the family of mitogen-activated protein kinases (MAPKs) and the transcription factors NF-kB and activator protein-1 (AP-1), are redox sensitive [181].…”

Increased ANG II sensitivity following recovery from acute kidney injury: role of oxidant stress in skeletal muscle resistance arteries

“…The fluorescence intensity of the central portion of the vessel was obtained in the absence of flow and every 5 min during 10 min of exposure to ANG II (10 Ϫ8 M). Acquired images were analyzed for fluorescence intensity in arbitrary units per minute using NIH Image software, and the rate of superoxide generation was calculated as the change in arbitrary units of fluorescent intensity per minute over the 30-min period normalized to the value in the absence of ANG II (33).…”

The effects of endothelial nitric oxide synthase gene polymorphisms on endothelial function and metabolic risk factors in healthy subjects: the significance of plasma adiponectin levels

“…Other data have indicated that flow-induced dilation in visceral fat arterioles is NO dependent in the absence of known coronary artery disease (9). Recent animal data suggested that endothelial nitric oxide synthase (eNOS) knockout mice presented with a phenotype of insulin resistance, hypertension, and dyslipidemia, resembling that observed in human metabolic syndrome, especially under nutritional stress (10,11).…”