Alterations in Nitric Oxide and Endothelin-1 Bioactivity Underlie Cerebrovascular Dysfunction in ApoE-Deficient Mice

Yamashiro, Kazuo; Milsom, Alexandra; Duchêne, Johan; Panayiotou, Catherine M; Urabe, Takao; Ahluwalia, Amrita

doi:10.1038/jcbfm.2010.34

Cited by 30 publications

(20 citation statements)

References 47 publications

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“…This peptide is a potent vasoconstrictor that is continuously secreted by vascular endothelial cells and acts on the underlying smooth muscle cells through ET A receptors that increase [Ca +2 ] c , [53-56], potentiating the TXA 2 pathway. It has been associated with many forms of cardiovascular disease [57, 58]. Based on this concept, and considering the evidence that conductance vessels from atherosclerotic apoE -/- mice exhibit an overproduction of ET-1 and ETA hypersensitivity [58-60], we evaluated the responsiveness in aortic rings from apoE -/- to ET-1.…”

Section: Discussionmentioning

confidence: 99%

“…It has been associated with many forms of cardiovascular disease [57, 58]. Based on this concept, and considering the evidence that conductance vessels from atherosclerotic apoE -/- mice exhibit an overproduction of ET-1 and ETA hypersensitivity [58-60], we evaluated the responsiveness in aortic rings from apoE -/- to ET-1. Our data show an exacerbated vascular contractile response to ET-1 in apoE -/- mice, which could also contribute (via NADPH oxidase) to the overproduction of •O 2 - and to the increased degree of endothelial dysfunction [53, 61] that we observed in the present study.…”

Section: Discussionmentioning

confidence: 99%

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Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice

Leal

Dias

Porto³

et al. 2017

Cell Physiol Biochem

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Background/Aims: The atherosclerotic apolipoprotein E-deficient (apoE^-/-) mouse exhibits impaired vasodilation and enhanced vasoconstriction responsiveness. The objectives of this study were: a) to determine the relative contribution of cyclooxygenases (Cox-1 and Cox-2), thromboxane A2 (TXA2) and endothelin-1 (ET-1) to enhancing vascular hyperresponsiveness in this model of atherosclerosis and b) to investigate the beneficial effects of the phosphodiesterase 5 inhibitor sildenafil on this endothelial dysfunction. Methods: Adult male apoE^-/- mice were treated with sildenafil (40 mg/kg/day, for 3 weeks) and compared with non-treated ApoE^-/- and wild-type mice. The beneficial effects of sildenafil on vascular contractile response to phenylephrine (PE) in aortic rings were evaluated before and after incubation with Cox-1 (SC-560) or Cox-2 (NS-398) inhibitors or the TP antagonist SQ-29548, and on contractile responsiveness to ET-1. Results: ApoE^-/- mice exhibited enhanced vasoconstriction to PE (R_max ∼35%, p<0.01), which was prevented by treatment with sildenafil. The enhanced PE-induced contractions were abolished by both Cox-1 inhibition and TP antagonist, but were not modified by Cox-2 inhibition. Aortic rings from ApoE^-/- mice also exhibited enhanced contractions to ET-1 (R_max ∼30%, p<0.01), which were attenuated in sildenafil-treated ApoE^-/- mice. In addition, we observed augmented levels of vascular proinflammatory cytokines in ApoE^-/- mice, which were partially corrected by treatment with sildenafil (IL-6, IL-10/IL-6 ratio and MCP-1). Conclusion: The present data show that the Cox-1/TXA2 pathway prevails over the Cox-2 isoform in the mediation of vascular hypercontractility observed in apoE^-/-mice. The results also show a beneficial effect of sildenafil on this endothelial dysfunction and on the proinflammatory cytokines in atherosclerotic animals, opening new perspectives for the treatment of other endothelium-related cardiovascular abnormalities.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice

Leal

Dias

Porto³

et al. 2017

Cell Physiol Biochem

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“…In apolipoprotein E-deficient mice, an animal model of atherosclerosis, a 2-week cilostazol treatment regimen normalized NOdependent cerebrovascular reactivity by restoring eNOSSer 1177 . 11 In cultured endothelial cells, it has been shown that cilostazol enhanced eNOS activity and NO production through AMP-activated protein kinase-dependent, cAMP/ protein kinase A-dependent, and phosphatidylinositol 3-kinase/Akt-dependent phosphorylation of eNOSSer 1177 . [22][23][24] Consistent with these findings, the present study demonstrated that chronic cilostazol treatment prevented hypertension-induced cerebrovascular dysfunction by maintaining eNOS-Ser 1177 .…”

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confidence: 99%

“…10 These beneficial effects of cilostazol have been attributed not only to its antiplatelet functions but also to other actions on the cerebrovascular endothelium. 11,12 Several studies showed that short-term pretreatment and post-treatment with cilostazol attenuated ischemic brain injury by increasing NO production and eNOS activation. [13][14][15] However, the comparative effects of cilostazol and aspirin on cerebrovascular function have not been investigated.…”

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confidence: 99%

Cilostazol, Not Aspirin, Reduces Ischemic Brain Injury via Endothelial Protection in Spontaneously Hypertensive Rats

Oyama

Yagita

Kawamura

et al. 2011

Stroke

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Background and Purpose-It is well-established that hypertension leads to endothelial dysfunction in the cerebral artery.Recently, cilostazol has been used for the secondary prevention of ischemic stroke. Among antiplatelet drugs, phosphodiesterase inhibitors including cilostazol have been shown to have protective effects on endothelial cells. The aim of the present study is to investigate the effects of cilostazol and aspirin on endothelial nitric oxide synthase (eNOS) phosphorylation in the cerebral cortex, endothelial function, and infarct size after brain ischemia in spontaneously hypertensive rats (SHR). Methods-Five-week-old male SHR received a 5-week regimen of chow containing 0.1% aspirin, 0.1% cilostazol, 0.3% cilostazol, or the vehicle control. The levels of total and Ser 1177 -phosphorylated eNOS protein in the cerebral cortex were evaluated by Western blot. To assess the contribution of eNOS in maintaining cerebral blood flow, we monitored cerebral blood flow by laser-Doppler flowmetry after L-N 5 -(1-iminoethyl)ornithine infusion. Additionally, we evaluated residual microperfusion using fluorescence-labeled serum protein and infarct size after transient focal brain ischemia. Results-In SHR, the blood pressure and heart rate were similar among the groups. Cilostazol-treated SHR had a significantly higher ratio of phospho-eNOS/total eNOS protein than vehicle-treated and aspirin-treated SHR. Treating with cilostazol, but not aspirin, significantly improved cerebral blood flow response to L-N 5 -(1-iminoethyl)ornithine. Cilostazol also increased residual perfusion of the microcirculation and reduced brain damage after ischemia compared to vehicle control and aspirin. Conclusions-These findings indicate that cilostazol, but not aspirin, can attenuate ischemic brain injury by maintaining endothelial function in the cerebral cortex of SHR. (Stroke. 2011;42:2571-2577.)Key Words: brain ischemia Ⅲ endothelial function Ⅲ hypertension Ⅲ phosphodiesterase-3 inhibitor H ypertension is one of the most important risk factors for cerebrovascular disease and is closely associated with endothelial dysfunction. Some studies observed endothelial dysfunction in patients with hypertension or cerebrovascular disease. 1,2 In hypertensive animal models, hypertension impairs endothelium-dependent vasodilatation, cerebrovascular autoregulation, and cerebral blood flow (CBF) responses, and it exacerbates ischemic brain damage. [3][4][5][6] Endothelial dysfunction is often characterized by a decrease in the bioavailability of endothelium-derived nitric oxide (NO). In endothelial cells, NO is produced by endothelial nitric oxide synthase (eNOS), and eNOS activity is regulated primarily by calcium-calmodulin activation and multisite phosphorylation of specific serine or threonine residues. Most importantly, phosphorylation of eNOS-Ser 1177 is thought to play a crucial role in eNOS activation. In a cerebral ischemia model, modification of the eNOS-Ser 1177 phosphorylation state modulated CBF and the outcome of ischemic injury. 7 Th...

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“…We detected reciprocal changes in eNOS phosphorylation at the positive and negative regulatory sites in ApoE À / À mice (i.e., reduced S1176 and increased T494 phosphorylation, respectively), exacerbated by HFD; consistent with previous reports total eNOS expression was not altered. 3,36 Taken together with our previous study showing that eNOS phosphorylation at S1179 (bovine, corresponding to mouse S1176 and human S1177) regulates the CBF deficit after stroke, 37 eNOS dysfunction is a plausible mechanism for larger perfusion defects Perfusion threshold for viability. The laser speckle contrast image of a representative ApoE À / À mouse shows pixels with r35% residual cerebral blood flow (CBF) superimposed in blue at 60 minutes after distal middle cerebral artery occlusion (arrowhead) immediately before reperfusion (upper left).…”

Section: Discussionmentioning

confidence: 77%

Hyperlipidemia Disrupts Cerebrovascular Reflexes and Worsens Ischemic Perfusion Defect

Ayata

Shin

Dileköz

et al. 2013

J Cereb Blood Flow Metab

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Hyperlipidemia is a highly prevalent risk factor for coronary and cervical atherosclerosis and stroke. However, even in the absence of overt atherosclerosis, hyperlipidemia disrupts endothelial and smooth muscle function. We investigated the impact of hyperlipidemia on resting-brain perfusion, fundamental cerebrovascular reflexes, and dynamic perfusion defect during acute focal ischemia in hyperlipidemic apolipoprotein E knockout mice before the development of flow-limiting atherosclerotic stenoses. Despite elevated blood pressures, absolute resting cerebral blood flow was reduced by 20% in apolipoprotein E knockout compared with wild type when measured by [ 14 C]-iodoamphetamine technique. Noninvasive, high spatiotemporal resolution laser speckle flow imaging revealed that the lower autoregulatory limit was elevated in apolipoprotein E knockout mice (60 vs. 40 mm Hg), and cortical hyperemic responses to hypercapnia and functional activation were attenuated by 30% and 64%, respectively. Distal middle cerebral artery occlusion caused significantly larger perfusion defects and infarct volumes in apolipoprotein E knockout compared with wild type. Cerebrovascular dysfunction showed a direct relationship to the duration of high-fat diet. These data suggest that hyperlipidemia disrupts cerebral blood flow regulation and diminishes collateral perfusion in acute stroke in the absence of hemodynamically significant atherosclerosis.

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Alterations in Nitric Oxide and Endothelin-1 Bioactivity Underlie Cerebrovascular Dysfunction in ApoE-Deficient Mice

Cited by 30 publications

References 47 publications

Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice

Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice

Cilostazol, Not Aspirin, Reduces Ischemic Brain Injury via Endothelial Protection in Spontaneously Hypertensive Rats

Hyperlipidemia Disrupts Cerebrovascular Reflexes and Worsens Ischemic Perfusion Defect

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