Roles of Endothelial Oxidases in Endothelium-derived Hyperpolarizing Factor Responses in Mice

Abstract

The endothelium synthesizes and releases several vasodilator substances, including prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). We have demonstrated that endothelium-derived hydrogen peroxide (H2O2) is an EDHF in animals and humans and that superoxide anions derived from endothelial nitric oxide synthases (NOSs) system are an important precursor for EDHF/H2O2 in mice. There are several intracellular sources of superoxide anions other than NOSs, including NAD(P)H oxidase, xanthine oxidase, lipoxygenase, and mitochondrial electron transport chain. In this study, we examined the possible role of endothelial oxidases other than NOSs in the EDHF-mediated responses. In angiotensin II-infused mice, both EDHF-mediated relaxations and hyperpolarizations to acetylcholine were significantly reduced, nitric oxide-mediated relaxations were rather enhanced, and vascular smooth muscle responses were preserved. Antihypertensive treatment normalized blood pressure but failed to improve EDHF-mediated responses in those mice. Acute inhibition of endothelial oxidases other than NOSs, including NAD(P)H oxidase, xanthine oxidase, lipoxygenase, or mitochondrial electron transport chain, had no inhibitory effects on EDHF-mediated responses. Furthermore, in p47phox-knockout mice, EDHF-mediated responses were unaltered. These results suggest that endothelial oxidases other than NOSs are not involved in EDHF/H2O2 responses in mice, suggesting a specific link between endothelial NOSs system and EDHF responses under physiological conditions.

Mechanisms for Enhanced Endothelium-Derived Hyperpolarizing Factor-Mediated Responses in Microvessels in Mice

“…15,22, 23 We found that among the eNOS phosphorylation sites, 33 phosphorylation at Ser1177 (stimulatory site) is significantly reduced and that at Thr495 (inhibitory site), it is significantly enhanced in mesenteric arteries compared with the aorta under basal conditions, indicating that eNOS is functionally suppressed in mesenteric arteries. In the present study, we did not examine the expression or affinity of endothelial muscarinic receptors, however, it is widely known that in both the aorta and mesenteric arteries, ACh couples to the muscarinic M3 receptor, 36,37 which is followed by an increase in [Ca 2+ ]i and Ca 2+ /CaM complex formation.…”

“…24, 25 There are several intracellular sources of superoxide anions other than NOSs, including nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase, xanthine oxidase, lipoxygenase, and the mitochondrial electron transport chain, but they are not involved in EDHF/H2O2 responses in mice. 23 In vivo, we have elucidated that EDHF/H2O2 plays an important role in coronary microcirculation, including coronary autoregulation, 19 cardiovascular protection against myocardial ischemia-perfusion injury 20 and metabolic coronary vasodilatation in canine coronary microcirculation in vivo. 26 Although it has been demonstrated that EDHF-mediated responses are dominant in microvessels, 7,8 the molecular mechanisms remain to be elucidated.…”

Erythropoietin enhances hydrogen peroxide-mediated dilatation of canine coronary collateral arterioles during myocardial ischemia in dogs in vivo

“…Based on previous reports (11,23,36,48), we chose the present doses of EPO, L-NMMA, catalase, IBTX, apamin, CTX, and wortmannin to examine their effects on coronary collateral vasodilatation during myocardial ischemia. We have previously confirmed the validity of the methods that we used in the present study (47).…”

“…Recently, Takaki et al (36) demonstrated that endothelial oxidases other than NOS are not involved in EDHF/H 2 O 2 responses in mice, suggesting a specific link between eNOS systems and EDHF responses under physiological conditions (36). H 2 O 2 is a relatively stable reactive oxygen intermediate and plays an important role in coronary autoregulation (48) and protection against myocardial ischemia-reperfusion injury (49).…”

Nitric Oxide as an Initiator of Brain Lesions During the Development of Alzheimer Disease

“…The role of EETs could be particularly important because, in addition to contributing to the maintenance of the basal tone and endothelium-dependent dilation of conduit arteries, it share many vascular protective properties with NO, suggesting that its alteration might be involved in the physiopathology of cardiovascular diseases. Another is likely H 2 O 2, known to stimulate potassium channel openings in a fashion similar to the EET (Park et al 2008;Takaki et al 2008). EET has anti-inflammatory properties, whereas H 2 O 2 may enhance inflammation and promote vascular hypertrophy.…”