Knockdown of angiopoietin like-2 protects against angiotensin II-induced cerebral endothelial dysfunction in mice

Yu, Carol; Luo, Xiaoyan; Duquette, Natacha; Thorin‐Trescases, Nathalie; Thorin, Éric

doi:10.1152/ajpheart.00278.2014

Cited by 12 publications

(20 citation statements)

References 43 publications

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“…To confirm these results, we measured the fluorescence associated with NO (DAF-2) and H 2 O 2 (DCFDA) release in isolated arteries 36,37 during FMD induced by a shear stress of 20 dyn/cm 2 , in both SP and PP conditions. In all conditions, fluorescence was extinguished by L-NNA confirming the unique involvement of eNOS in FMD ( Figure 3).…”

Section: Impact Of Pulsatile Pressure On Myogenic Tonementioning

confidence: 86%

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Pulse pressure-dependent cerebrovascular eNOS regulation in mice

Raignault

Bolduc

Lesage

et al. 2016

J Cereb Blood Flow Metab

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Arterial blood pressure is oscillatory; whether pulse pressure (PP) regulates cerebral artery myogenic tone (MT) and endothelial function is currently unknown. To test the impact of PP on MT and dilation to flow (FMD) or to acetylcholine (Ach), isolated pressurized mouse posterior cerebral arteries were subjected to either static pressure (SP) or a physiological PP (amplitude: 30 mm Hg; frequency: 550 bpm). Under PP, MT was significantly higher than in SP conditions (p < 0.05) and was not affected by eNOS inhibition. In contrast, under SP, eNOS inhibition increased (p < 0.05) MT to levels observed under PP, suggesting that PP may inhibit eNOS. At a shear stress of 20 dyn/cm 2 , FMD was lower (p < 0.05) under SP than PP. Under SP, eNOS-dependent O À 2 =H 2 O 2 production contributed to FMD, while under PP, eNOS-dependent NO was responsible for FMD, indicating that PP favours eNOS coupling. Differences in FMD between pressure conditions were abolished after NOX2 inhibition. In contrast to FMD, Ach-induced dilations were higher (p < 0.05) under SP than PP. Reactive oxygen species scavenging reduced (p < 0.05) Ach-dependent dilations under SP, but increased (p < 0.05) them under PP; hence, under PP, Ach promotes ROS production and limits eNOS-derived NO activity. In conclusion, PP finely regulates eNOS, controlling cerebral artery reactivity.

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Section: Impact Of Pulsatile Pressure On Myogenic Tonementioning

confidence: 86%

“…27,36,37 Arterial segments were incubated with or without L-NNA (100 lmol/L) or PEGcatalase (100 U/mL) for 30 min, washed three times with PSS, pre-constricted with phenylephrine and then exposed to a shear stress of 20 dyn/cm 2 ; during the dilation, NO-or H 2 O 2 -fluorescence was quantified.…”

Section: Fluorescence Studiesmentioning

confidence: 99%

Pulse pressure-dependent cerebrovascular eNOS regulation in mice

Raignault

Bolduc

Lesage

et al. 2016

J Cereb Blood Flow Metab

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“…Several studies have correlated the levels of angiopoietin-1 and -2 with cerebral malaria severity and survival (37,(39)(40)(41). Interestingly, a relation between AT1/AT2 activity and angiopoietin-2 levels has been described in endothelial cells (42,43), possibly mediated by VEGF (44,45), that may link the activities of both pathways in vivo.…”

Section: Immortalization and Culture Of Hbmecs And Other Endothelial mentioning

confidence: 99%

Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria

Gállego-Delgado¹,

Basu-Roy²,

Ty³

et al. 2016

Journal of Clinical Investigation

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Cerebral malaria is characterized by cytoadhesion of Plasmodium falciparum-infected red blood cells (Pf-iRBCs) to endothelial cells in the brain, disruption of the blood-brain barrier, and cerebral microhemorrhages. No available antimalarial drugs specifically target the endothelial disruptions underlying this complication, which is responsible for the majority of malaria-associated deaths. Here, we have demonstrated that ruptured Pf-iRBCs induce activation of β-catenin, leading to disruption of inter-endothelial cell junctions in human brain microvascular endothelial cells (HBMECs). Inhibition of β-catenin-induced TCF/LEF transcription in the nucleus of HBMECs prevented the disruption of endothelial junctions, confirming that β-catenin is a key mediator of P. falciparum adverse effects on endothelial integrity. Blockade of the angiotensin II type 1 receptor (AT1) or stimulation of the type 2 receptor (AT2) abrogated Pf-iRBC-induced activation of β-catenin and prevented the disruption of HBMEC monolayers. In a mouse model of cerebral malaria, modulation of angiotensin II receptors produced similar effects, leading to protection against cerebral malaria, reduced cerebral hemorrhages, and increased survival. In contrast, AT2-deficient mice were more susceptible to cerebral malaria. The interrelation of the β-catenin and the angiotensin II signaling pathways opens immediate host-targeted therapeutic possibilities for cerebral malaria and other diseases in which brain endothelial integrity is compromised.

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“…Little is known about the impact of angptl2 on endothelial function and vice versa . We, and others, reported that recombinant angptl2 significantly reduced acetylcholine-induced dilation of isolated mouse arteries and, conversely, that angptl2 knockdown or knockout mice were protected against endothelial dysfunction induced by a high-fat diet [ 18 , 27 ] and chronic infusion of low dose angiotensin II [ 41 ]. Altogether, these data suggest that angptl2 could be a marker of endothelial function.…”

Section: Discussionmentioning

confidence: 99%

Exercise Lowers Plasma Angiopoietin-Like 2 in Men with Post-Acute Coronary Syndrome

Thorin‐Trescases

Hayami

et al. 2016

PLoS ONE

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Pro-inflammatory angiopoietin-like 2 (angptl2) promotes endothelial dysfunction in mice and circulating angptl2 is higher in patients with cardiovascular diseases. We previously reported that a single bout of physical exercise was able to reduce angptl2 levels in coronary patients. We hypothesized that chronic exercise would reduce angptl2 in patients with post-acute coronary syndrome (ACS) and endothelial dysfunction. Post-ACS patients (n = 40, 10 women) were enrolled in a 3-month exercise-based prevention program. Plasma angptl2, hs-CRP, and endothelial function assessed by scintigraphic forearm blood flow, were measured before and at the end of the study. Exercise increased VO2peak by 10% (p<0.05), but did not significantly affect endothelial function, in both men and women. In contrast, exercise reduced angptl2 levels only in men (-26±7%, p<0.05), but unexpectedly not in women (+30±16%), despite similar initial levels in both groups. Exercise reduced hs-CRP levels in men but not in women. In men, levels of angptl2, but not of hs-CRP, reached at the end of the training program were negatively correlated with VO2peak (r = -0.462, p = 0.012) and with endothelial function (r = -0.419, p = 0.033) measured at baseline: better initial cardiopulmonary fitness and endothelial function correlated with lower angptl2 levels after exercise. Pre-exercise angptl2 levels were lower if left ventricular ejection time was long (p<0.05) and the drop in angptl2 induced by exercise was greater if the cardiac output was high (p<0.05). In conclusion, in post-ACS men, angptl2 levels are sensitive to chronic exercise training. Low circulating angptl2 reached after training may reflect good endothelial and cardiopulmonary functions.

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Knockdown of angiopoietin like-2 protects against angiotensin II-induced cerebral endothelial dysfunction in mice

Cited by 12 publications

References 43 publications

Pulse pressure-dependent cerebrovascular eNOS regulation in mice

Pulse pressure-dependent cerebrovascular eNOS regulation in mice

Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria

Exercise Lowers Plasma Angiopoietin-Like 2 in Men with Post-Acute Coronary Syndrome

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