An acute rise in intraluminal pressure shifts the mediator of flow-mediated dilation from nitric oxide to hydrogen peroxide in human arterioles

Abstract

Endothelial nitric oxide (NO) is the primary mediator of flow-mediated dilation (FMD) in human adipose microvessels. Impaired NO-mediated vasodilation occurs after acute and chronic hypertension, possibly due to excess generation of reactive oxygen species (ROS). The direct role of pressure elevation in this impairment of human arteriolar dilation is not known. We tested the hypothesis that elevation in pressure is sufficient to impair FMD. Arterioles were isolated from human adipose tissue and cannulated, and vasodilation to graded flow gradients was measured before and after exposure to increased intraluminal pressure (IILP; 150 mmHg, 30 min). The mediator of FMD was determined using pharmacological agents to reduce NO [N(G)-nitro-l-arginine methyl ester (l-NAME), 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO)], or H2O2 [polyethylene glycol (PEG)-catalase], and mitochondrial (mt) ROS was quantified using fluorescence microscopy. Exposure to IILP decreased overall FMD (max %dilation: 82.7 ± 4.9 vs. 62 ± 5.6; P < 0.05). This dilation was abolished by treatment with l-NAME prepressure and PEG-catalase after IILP (max %dilation: l-NAME: 23.8 ± 6.1 vs. 74.8 ± 8.6; PEG-catalase: 71.8 ± 5.9 vs. 24.6 ± 10.6). To examine if this change was mediated by mtROS, FMD responses were measured in the presence of the complex I inhibitor rotenone or the mitochondrial antioxidant mitoTempol. Before IILP, FMD was unaffected by either compound; however, both inhibited dilation after IILP. The fluorescence intensity of mitochondria peroxy yellow 1 (MitoPY1), a mitochondria-specific fluorescent probe for H2O2, increased during flow after IILP (%change from static: 12.3 ± 14.5 vs. 127.9 ± 57.7). These results demonstrate a novel compensatory dilator mechanism in humans that is triggered by IILP, inducing a change in the mediator of FMD from NO to mitochondria-derived H2O2.

Modulation of the myogenic mechanism: concordant effects of NO synthesis inhibition and O2− dismutation on renal autoregulation in the time and frequency domains

“…The potentiation was inhibited by tempol in the presence or absence of polyethylene glycol catalase (26), indicating a primary action of O 2 Ϫ rather than H 2 O 2 . Moreover, H 2 O 2 commonly acts as vasodilator in circulatory beds, such as cerebral, coronary, mesenteric, and skeletal muscle, and may function as an endotheliumdependent hyperpolarization factor and an activator of potassium channels (10,14,47,55,64,70); both dilator and hyperpolarizing actions are expected to blunt rather than potentiate pressure-induced myogenic constriction.…”

Improved arterial flow-mediated dilation after exertion involves hydrogen peroxide in overweight and obese adults following aerobic exercise training

“…Approximately 2 ml of fat tissue was removed and transferred to (48C) HEPES buffer solution. Following dissection, cannulation, and equilibration at physiological pressure and temperature, dilation of microvessels was observed via video microscopy, as described previously and in Supplementary material, http://links.lww.com/HJH/A617 [11,12,22,23]. After intraluminal pressure of 60 cm H 2 O was maintained for 30 min, vessels were constricted 30-50% with endothelin-1 (100-200 pmol final concentrations).…”

Pulse pressure-dependent cerebrovascular eNOS regulation in mice

“…23 This was confirmed by two studies showing that in rat-isolated coronary arterioles 24 and mesenteric arteries, 22 cellular deformation induced by pressure, stretch and wall shear stress, potentiated the release of NO resulting in dilation, despite an increase in ROS production. However, Gutterman's group recently reported that in pressurized human peripheral arterioles, a severe increase in intravascular pressure for 30 min induced either ex vivo (in static conditions) 25 or in vivo (in pulsatile conditions), 26 promoted endothelial dysfunction evidenced by reduced eNOS-dependent NO activity and excessive ROS production. Therefore, both a lack of pulsatile pressure and its excess are damaging to the endothelium as they both impair NO-dependent dilations.…”