scholarly journals NADPH oxidase 4 has a crucial impact on the microcirculation of hypercholesteremic LDL receptor deficient mice

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
P Diaba-Nuhoho ◽  
A Shahid ◽  
C Brunssen ◽  
H Morawietz ◽  
H Brendel
Keyword(s):  
Blood Pressure ◽  
Endothelial Dysfunction ◽  
Mouse Model ◽  
Nadph Oxidase ◽  
Endothelial Function ◽  
Vascular Function ◽  
Mesenteric Arteries ◽  
Resistance Arteries ◽  
Enos Expression ◽  
Small Resistance

Abstract Introduction NADPH oxidase (NOX) 4-generated H2O2 has anti-atherosclerotic properties in conduit arteries like the aorta and carotids. However, the role of NOX4 on vascular function of small resistance arteries and blood pressure in a mouse model of familial hypercholesterolemia is unknown. Purpose We evaluated whether NOX4-generated H2O2 might play a role in perivascular adipose tissue of the thoracic aorta (tPVAT) and small resistance arteries on vascular function in a mouse model of familial hypercholesterolemia. Methods Aortic segments and mesenteric arteries from 26-week-old Ldlr−/− and Nox4−/− / Ldlr−/− mice were analysed by Mulvany myograph. In addition, vascular contraction and relaxation was analysed in the presence of L-NAME and catalase. Analysis of mRNA expression was performed in murine and human tissue by quantitative real-time PCR. Blood pressure was detected by tail cuff method in conscious, trained mice. Results Loss of NOX4 led to severe endothelial dysfunction in mesenteric arteries of Ldlr−/− mice. Blocking of NO synthases with L-NAME led to decreased endothelial relaxation in Ldlr−/− mice at the level of Nox4−/− / Ldlr−/− mice. However, incubation with L-NAME did not worsen the established endothelial dysfunction of the mesenteric arteries from Nox4−/− / Ldlr−/− mice. These results are strikingly different from the aorta, where inhibition of NO synthases led to a similarly impaired endothelial relaxation in both mouse strains. We detected a similar eNOS expression in the aorta of Ldlr−/− and Nox4−/− / Ldlr−/−, but a reduced eNOS expression in the mesenteric arteries of Nox4−/− / Ldlr−/− mice. H2O2 can induce eNOS expression. Therefore, we analysed the vascular function after catalase incubation and again found a significant reduction of endothelial function in the mesenteric arteries of Ldlr−/− mice. Finally, we analysed blood pressure of these mice and did not observe differences in systolic blood pressure, despite significant differences in endothelial function of resistant arteries. Conclusion NOX4 protects against severe endothelial dysfunction in the mesenteric artery in a model of hypercholesterolemia. FUNDunding Acknowledgement Type of funding sources: Other. Main funding source(s): Ghanaian-German postgraduate training scholarship program (DAAD)

Abstract 55: Hiv Viral Proteins Elevate Blood Pressure And Impairs Endothelial Function In Resistance Arteries Via Sex Specific, Immune And Nox1-dependent Mechanisms In Mice.

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Taylor Kress
Keyword(s):  
Blood Pressure ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Viral Infection ◽  
Immune Cells ◽  
Vascular Reactivity ◽  
Radio Telemetry ◽  
Viral Proteins ◽  
Mesenteric Arteries ◽  
Resistance Arteries

Thanks to the onset of combination antiretroviral therapy (cART), patients living with HIV live longer but experience accelerated rates of hypertension. However, the etiology of HIV-associated hypertension remains ill defined, specifically the respective contributions of repressed viral infection and cART treatment. Herein, we took advantage of a transgenic model (Tg26) of repressed viral infection to investigate the contribution of HIV viral proteins to hypertension. Quantification of inflammatory cytokines revealed elevated circulating TNFα levels but also high aorta and intraperitoneal immune cells TNFα in male Tg26 mice leading to the hypothesis that HIV-associated hypertension involves immune-derived TNFα secretion and endothelial dysfunction in males and females Tg26 mice. Blood pressure (BP) was measured via radio telemetry and vascular reactivity studies performed via wire myography. BP analysis revealed increased mean arterial pressure (MAP: male: WT=112.3±1.3 vs Tg26=121.9±4.0 mmHg/ female: WT=110.6±3.01/ Tg26=120.3±6.9 mmHg) and heart rate in both sexes (P<0.05). However, blockade of TNFα action with etanercept restored BP and aortic endothelial function in male Tg26 mice only. Along with an increase in TNFα, male Tg26 aortas showed infiltration of Tcells and proinflammatory cytokines IL-18, and IL-6, which were not seen in females. However, scavenging of reactive oxygen species with the selective NOX1 inhibitor GKT771 restored aorta endothelial function in both sexes. A contributor to hypertension is impaired endothelial relaxation in resistance arteries. Mesenteric arteries showed impaired endothelial relaxation to acetylcholine in both male and female Tg26 mice (P<0.05) with no impairment in smooth muscle cell relaxation. This phenotype was reproduced in WT mice transplanted with Tg26 bone marrow (BM) and remarkably reversed in Tg26 mice receiving WT BM supporting a clear role for immune cells in endothelial dysfunction. Collectively, these data indicate that HIV-related hypertension involves immune and NOX1-dependent endothelial dysfunction in both sexes but TNFα-dependent mechanisms in males only providing evidence of sex specific mechanisms.

scholarly journals Endothelial dysfunction in small arteries and early signs  of atherosclerosis in ApoE knockout rats

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Simin Berenji Ardestani ◽  
Ingrid Eftedal ◽  
Michael Pedersen ◽  
Per Bendix Jeppesen ◽  
Rikke Nørregaard ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Early Stage ◽  
Western Diet ◽  
Mesenteric Arteries ◽  
Standard Diet ◽  
Resistance Arteries ◽  
Small Resistance ◽  
Apoe Ko

Abstract Endothelial dysfunction is recognized as a major contributor to atherosclerosis and has been suggested to be evident far before plaque formation. Endothelial dysfunction in small resistance arteries has been suggested to initiate long before changes in conduit arteries. In this study, we address early changes in endothelial function of atherosclerosis prone rats. Male ApoE knockout (KO) rats (11- to 13-weeks-old) were subjected to either a Western or standard diet. The diet intervention continued for a period of 20–24 weeks. Endothelial function of pulmonary and mesenteric arteries was examined in vitro using an isometric myograph. We found that Western diet decreased the contribution of cyclooxygenase (COX) to control the vascular tone of both pulmonary and mesenteric arteries. These changes were associated with early stage atherosclerosis and elevated level of plasma total cholesterol, LDL and triglyceride in ApoE KO rats. Chondroid-transformed smooth muscle cells, calcifications, macrophages accumulation and foam cells were also observed in the aortic arch from ApoE KO rats fed Western diet. The ApoE KO rats are a new model to study endothelial dysfunction during the earlier stages of atherosclerosis and could help us improve preclinical drug development.

scholarly journals Altered Purinergic Receptor Sensitivity in Type 2 Diabetes-Associated Endothelial Dysfunction and Up4A-Mediated Vascular Contraction

2018 ◽  
Vol 19 (12) ◽  
pp. 3942 ◽  
Author(s):  
Ali Mahdi ◽  
Tong Jiao ◽  
Yahor Tratsiakovich ◽  
Jiangning Yang ◽  
Claes-Göran Östenson ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Function ◽  
Purinergic Receptor ◽  
Purinergic Signaling ◽  
Mesenteric Arteries ◽  
Vascular Contraction ◽  
Gk Rats ◽  
Vasoconstrictor Response

Purinergic signaling may be altered in diabetes accounting for endothelial dysfunction. Uridine adenosine tetraphosphate (Up4A), a novel dinucleotide substance, regulates vascular function via both purinergic P1 and P2 receptors (PR). Up4A enhances vascular contraction in isolated arteries of diabetic rats likely through P2R. However, the precise involvement of PRs in endothelial dysfunction and the vasoconstrictor response to Up4A in diabetes has not been fully elucidated. We tested whether inhibition of PRs improved endothelial function and attenuated Up4A-mediated vascular contraction using both aortas and mesenteric arteries of type 2 diabetic (T2D) Goto Kakizaki (GK) rats vs. control Wistar (WT) rats. Endothelium-dependent (EDR) but not endothelium-independent relaxation was significantly impaired in both aortas and mesenteric arteries from GK vs. WT rats. Non-selective inhibition of P1R or P2R significantly improved EDR in aortas but not mesenteric arteries from GK rats. Inhibition of A1R, P2X7R, or P2Y6R significantly improved EDR in aortas. Vasoconstrictor response to Up4A was enhanced in aortas but not mesenteric arteries of GK vs. WT rats via involvement of A1R and P2X7R but not P2Y6R. Depletion of major endothelial component nitric oxide enhanced Up4A-induced aortic contraction to a similar extent between WT and GK rats. No significant differences in protein levels of A1R, P2X7R, and P2Y6R in aortas from GK and WT rats were observed. These data suggest that altered PR sensitivity accounts for endothelial dysfunction in aortas in diabetes. Modulating PRs may represent a potential therapy for improving endothelial function.

Previous gestational diabetes impairs long-term endothelial function in a mouse model of complicated pregnancy

2010 ◽  
Vol 299 (3) ◽  
pp. R862-R870 ◽  
Author(s):  
Joanna L. Stanley ◽  
Sowndramalingam Sankaralingam ◽  
Philip N. Baker ◽  
Sandra T. Davidge
Keyword(s):  
Endothelial Dysfunction ◽  
Gestational Diabetes ◽  
Mouse Model ◽  
Endothelial Function ◽  
Fluorescence Intensity ◽  
Mean Fluorescence Intensity ◽  
Mesenteric Arteries ◽  
Superoxide Production ◽  
Increased Risk

Women who develop gestational diabetes mellitis (GDM) display endothelial dysfunction up to 1 yr after pregnancy, despite a return to normoglycemia. It is unknown whether this dysfunction was preexisting or whether GDM pregnancy leads to long-term endothelial dysfunction. A mouse model that spontaneously develops GDM ( Lepr db/+) was used to determine whether the endothelial dysfunction that develops during GDM is evident in later life. Heterozygous and wild-type (WT) controls were allowed to litter once, then age to 9–10 mo, and were compared with virgin controls. Vascular function of small mesenteric arteries was assessed using wire myography. Concentration response curves to the thromboxane A2mimetic U46619 and the endothelium-dependent vasodilator methacholine were constructed. Superoxide production and peroxynitrite formation was also measured. Mice with previous GDM displayed blood glucose concentrations similar to previously pregnant WT mice (8.0 ± 0.1 vs. 7.1 ± 0.3 mmol/l, P > 0.05). Arteries from mice with previous GDM displayed increased sensitivity to U46619 (EC50 5.2 ± 0.7 vs. 45.2 ± 1.0 nmol/l, P < 0.01) and impaired endothelium-dependent relaxation compared with WT controls (29 ± 8 vs. 58 ± 16 percent relaxation, P < 0.05). This was associated with increased superoxide production (93.3 ± 2.3 vs. 64.6 ± 1.6 mean fluorescence intensity, P < 0.001) and increased peroxynitrite formation (173.5 ± 11.0 vs. 57.4 ± 16.2 mean fluorescence intensity, P < 0.01) compared with virgin controls. In summary, endothelial dysfunction was evident in mice with previous GDM compared with previously healthy pregnant mice or virgin controls. These data suggest that GDM affects endothelial function and may contribute to an increased risk of cardiovascular disease.

scholarly journals Transglutaminase 2 Inhibitor LDN 27219 Age-Dependently Lowers Blood Pressure and Improves Endothelium-Dependent Vasodilation in Resistance Arteries

Hypertension ◽  
2021 ◽  
Vol 77 (1) ◽  
pp. 216-227 ◽  
Author(s):  
Estéfano Pinilla ◽  
Simon Comerma-Steffensen ◽  
Judit Prat-Duran ◽  
Luis Rivera ◽  
Vladimir V. Matchkov ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Potassium Channels ◽  
Vascular Function ◽  
Transglutaminase 2 ◽  
Mesenteric Arteries ◽  
Resistance Arteries ◽  
Closed Conformation ◽  
Open Conformation ◽  
Age Related

Transglutaminase 2 (TG2) is an enzyme which in the open conformation exerts transamidase activity, leading to protein cross-linking and fibrosis. In the closed conformation, TG2 participates in transmembrane signaling as a G protein. The unspecific transglutaminase inhibitor cystamine causes vasorelaxation in rat resistance arteries. However, the role of TG2 conformation in vascular function is unknown. We investigated the vascular effects of selective TG2 inhibitors by myography in isolated rat mesenteric and human subcutaneous resistance arteries, patch-clamp studies on vascular smooth muscle cells, and blood pressure measurements in rats and mice. LDN 27219 promoted the closed TG2 conformation and inhibited transamidase activity in mesenteric arteries. In contrast to TG2 inhibitors promoting the open conformation (Z-DON, VA5), LDN 27219 concentration-dependently relaxed rat and resistance human arteries by a mechanism dependent on nitric oxide, large-conductance calcium-activated and voltage-gated potassium channels 7, lowering blood pressure. LDN 27219 also potentiated acetylcholine-induced relaxation by opening potassium channels in the smooth muscle; these effects were abolished by membrane-permeable TG2 inhibitors promoting the open conformation. In isolated arteries from 35- to 40-week-old rats, transamidase activity was increased, and LDN 27219 improved acetylcholine-induced relaxation more than in younger rats. Infusion of LDN 27219 decreased blood pressure more effectively in 35- to 40-week than 12- to 14-week-old anesthetized rats. In summary, pharmacological modulation of TG2 to the closed conformation age-dependently lowers blood pressure and, by opening potassium channels, potentiates endothelium-dependent vasorelaxation. Our findings suggest that promoting the closed conformation of TG2 is a potential strategy to treat age-related vascular dysfunction and lowers blood pressure.

Alteration of perivascular adipose tissue function in angiotensin II-induced hypertension

2009 ◽  
Vol 87 (11) ◽  
pp. 944-953 ◽  
Author(s):  
Robert M.K.W. Lee ◽  
Lili Ding ◽  
Chao Lu ◽  
Li-Ying Su ◽  
Yu-Jing Gao
Keyword(s):  
Blood Pressure ◽  
Adipose Tissue ◽  
Angiotensin Ii ◽  
Vascular Function ◽  
Wistar Rats ◽  
Mesenteric Arteries ◽  
Resistance Arteries ◽  
Hypertensive Rats ◽  
Perivascular Adipose Tissue ◽  
And Control

We studied the role of perivascular adipose tissue (PVAT) in the control of vascular function in an in vivo experimental model of hypertension produced by angiotensin II infusion by osmotic minipump in adult male Wistar rats. Two weeks after infusion with angiotensin II, blood pressure in treated rats was significantly elevated but heart rate was reduced compared with control rats infused with physiological saline. Contraction of aorta from the 2 groups of rats in response to phenylephrine or serotonin was significantly attenuated by the presence of PVAT in both the presence and absence of endothelium. This attenuation effect on contraction to phenylephrine was higher, however, in vessels from control rats than in vessels from hypertensive rats in the absence of endothelium. In the mesenteric resistance arteries, lumen diameter was larger in both hypertensive and control vessels with intact PVAT than in vessels with PVAT removed. The medial wall was thicker in arteries from hypertensive rats. The presence of PVAT potentiated the contraction induced by KCl in mesenteric arteries from control rats, but not in hypertensive rats. PVAT also attenuated the contraction of mesenteric arteries in response to phenylephrine or serotonin in both hypertensive and control groups. Mesenteric arteries from hypertensive rats were more responsive to stimulation by serotonin than those from control rats. We conclude that the increased blood pressure of Wistar rats that occurred after infusion with angiotensin II was associated with changes in the functions of PVAT in the aorta and mesenteric arteries and in the structure and function of resistance arteries.

The mechanism of resveratrol-induced vasorelaxation differs in the mesenteric resistance arteries of lean and obese rats

2000 ◽  
Vol 100 (1) ◽  
pp. 55-60 ◽  
Author(s):  
Ebrahim K. NADERALI ◽  
Sharon L. SMITH ◽  
Patrick J. DOYLE ◽  
Gareth WILLIAMS
Keyword(s):  
Methyl Ester ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Mesenteric Arteries ◽  
Resistance Arteries ◽  
Rightward Shift ◽  
Endothelial Denudation ◽  
Obese Rats

Resveratrol has been shown to induce vasorelaxation. In this study, we investigated the mechanism(s) of resveratrol-induced vasorelaxation in resistance mesenteric arteries from male lean and dietary-induced obese rats. Compared with lean rats, arteries from dietary-obese rats showed significant (P < 0.001) endothelial dysfunction, as indicated by a decrease (> 20%) in maximal acetylcholine-induced vasorelaxation. Resveratrol (5–35 µmol/l) induced concentration-dependent relaxation of mesenteric arteries preconstricted with noradrenaline (8 µmol/l) or KCl (125 mmol/l) from both lean and dietary-obese rats. There were no significant differences between the two groups, achieving a maximum relaxation of > 95% at a concentration of 35 µmol/l. In noradrenaline-preconstricted arteries from lean rats, NG-nitro-L-arginine methyl ester (L-NAME; 100 and 300 µmol/l) caused a significant (P < 0.01) concentration-dependent rightward shift in reseveratrol activity, with no effect on maximal responses. However, L-NAME (100 and 300 µmol/l) did not alter the effects of reseveratrol on arteries from dietary-obese rats, giving superimposed concentration–responses curves. Indomethacin was also ineffective in altering resveratrol activity in arteries from both lean and dietary-obese rats. In noradrenaline-precontracted arteries from dietary-obese rats, responses to resveratrol were not attenuated by endothelial denudation, indicating an action independent of the endothelium. This study indicates that: (a) the maximal effects of resveratrol on resistance arteries from lean and dietary-obese rats are not effected by endothelial dysfunction, and (b) the effects of resveratrol in lean animals (where endothelial function is not impaired), but not in dietary-obese rats, are mediated via NO.

scholarly journals Transmission of raised blood pressure and endothelial dysfunction to the F2generation induced by maternal protein restriction in the F0, in the absence of dietary challenge in the F1generation

2008 ◽  
Vol 100 (4) ◽  
pp. 760-766 ◽  
Author(s):  
Christopher Torrens ◽  
Lucilla Poston ◽  
Mark A. Hanson
Keyword(s):  
Blood Pressure ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Protein Restriction ◽  
Mesenteric Arteries ◽  
Maximal Response ◽  
Maternal Line ◽  
Maternal Protein Restriction ◽  
Female Wistar Rats ◽  
Protein Restricted Diet

We have previously demonstrated that maternal protein restriction during pregnancy leads to raised blood pressure and endothelial dysfunction in the offspring (F1). Here we show that these characteristics are transmitted to the F2offspring through the maternal line, in the absence of any additional challenges to the F1. Female Wistar rats were fed either a control (18 % casein) or protein-restricted diet (PR; 9 % casein) throughout pregnancy. Female F1offspring, maintained on standard chow postpartum, were mated with breeding males to produce F2progeny. Systolic blood pressure (SBP) in male F2offspring was assessed by tail-cuff plethysmography at age 100 d and vascular function of small mesenteric arteries by wire myography at age 80 and 200 d. SBP was raised in PR F2offspring compared with controls (control 122·1 (sem2·3) mmHg,n7; PR 134·7 (sem3·2) mmHg,n6;P < 0·01) and endothelial function, assessed by vasodilatation to acetylcholine, was impaired at both age 80 d (% maximal response: control 89·7 (sem2·6),n14; PR 72·7 (sem4·4),n15;P < 0·01) and 200 d (effective concentration equal to 50 % of maximum (pEC50): control 7·67 (sem0·10),n10; PR 7·33 (sem0·07),n8;P < 0·05). The present study demonstrates that both raised blood pressure and endothelial dysfunction are passed via the maternal line to grand-offspring in the absence of any additional dietary challenges to their F1mothers. Risk factors for chronic disease may therefore be heritable by non-genomic processes.

Abstract P061: Effects of Black Tea With and Without a Fat Load on Vascular Function in Mildly Hypertensive Subjects

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Davide Grassi ◽  
Richard Draijer ◽  
Giovambattista Desideri ◽  
Theo Mulder ◽  
Claudio Ferri
Keyword(s):  
Blood Pressure ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Function ◽  
Black Tea ◽  
Stiffness Index ◽  
Maximal Response ◽  
Tea Consumption ◽  
Double Blind ◽  
Reflection Index

Introduction: Endothelial dysfunction is an early biomarker for the development of cardiovascular disease and a predictor of future cardiovascular events. A number of intervention studies in healthy and diseased subjects have reported that endothelial function, as assessed by flow-mediated vasodilation (FMD), is positively affected by black tea consumption. On the other hand, high calorie fatty meals are detrimental to endothelial function. Hypothesis: To assess the effect of black tea with and without a fat load on FMD, digital volume pulse (DVP) and office blood pressure (BP) in never treated grade 1 hypertensive subjects without additional cardiovascular risk factors. Methods: According to a randomized, double-blind, controlled, cross-over design, 19 grade 1 hypertensives were assigned to consume black tea, containing 150 mg polyphenols or a placebo drink matched for caffeine, color and taste, twice a day for eight days, with a wash-out period in between of 13 days. On day 7 all measurements were performed in a fasted state, while on day 8 subjects consumed ultra-heat-treated whipping cream (1 gram fat per kg bodyweight) 30 minutes after consuming the test products. FMD, DVP and BP were measured at baseline and 1, 2, 3 and 4 hours after consumption of the test products. Results: Baseline FMD improved after 1-week tea consumption when compared to placebo (p<0.0001). An additional cup of tea further increased FMD at 1, 2, 3 and 4 hours after consumption when compared to baseline with maximal response 2 hours after intake (p<0.0001). Fat challenge significantly decreased FMD (p<0.0001), which was counteracted by tea consumption. Tea improved reflection index (small vessel tone; p<0.0001) and stiffness index (large arterial stiffness; p<0.0001) with additional effects after acute tea consumption with and without fat load. Further, tea decreased systolic and diastolic BP with and without a fat load (all p<0.0001). Conclusions: We demonstrate for the first time that moderate consumption of black tea protects against oral fat load-induced endothelial dysfunction in hypertensive but otherwise healthy subjects. The vascular benefits of tea are also reflected in improved endothelial function and peripheral arterial hemodynamics as well as blood pressure lowering under fasted and postprandial conditions. Our findings are of clinical relevance and interest, considering that the ingestion of the main daily meal has been suggested to be a trigger for acute myocardial infarction.

scholarly journals Sortilin evokes endothelial dysfunction and arterial hypertension through the dysregulation of sphingolipid metabolism and oxidative stress

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
P Di Pietro ◽  
M Oliveti ◽  
E Sommella ◽  
A Damato ◽  
A Puca ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Endothelial Cells ◽  
Nadph Oxidase ◽  
Endothelial Function ◽  
Acid Sphingomyelinase ◽  
Mesenteric Arteries ◽  
Hypertensive Patients ◽  
Arterial Blood ◽  
Sphingosine 1 Phosphate

Abstract Background Sortilin, a member of vacuolar protein sorting domain family Vps10, has been positively correlated with vascular and metabolic disorders in humans. Previous study has shown that, in response to Fas receptor stimulation, sortilin together with acid sphingomyelinase (ASMase) promote the clustering of lipid rafts and subsequent activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in coronary endothelial cells. However, whether sortilin plays a role in endothelial cells function is currently unknown. Purpose To assess whether sortilin per se was able to influence vascular function, thereby contributing to the pathogenesis of cardiovascular diseases. Methods Pressure myography was used to study vascular reactivity of mesenteric arteries. To investigate the involvement of acid sphingomyelinase (ASM), we performed gene silencing approach and fluorometric activity assay. NADPH oxidase lucigenin assay was used to evaluate oxidative stress in endothelial cells and resistance vessels. The effects of circulating sortilin on cardiovascular system was evaluated by systemic delivery of recombinant sortilin protein to wild-type (WT), sphingosine-1-phosphate receptor 3 (S1P3) and NADPH oxidase 2 (gp91phox/NOX2) deficient mice. Systolic arterial blood pressure (SBP) was noninvasively registered in conscious mice by tail-cuff blood monitoring. Finally, to explore the translational relevance of sortilin, we measured sortilin and NOX2 soluble derived peptide levels using ELISA and quantified sphingosine-1-phosphate (S1P) by liquid chromatography–tandem mass spectrometry (LC-MS/MS) in plasma of hypertensive patients. Results Here we demonstrated that sortilin evoked endothelial dysfunction in mesenteric arteries due to increased NADPH oxidase-derived oxidative stress. Knockdown of ASM successfully prevented impairment of endothelial function. Using the inhibitor of sphingosine kinase type 1 (SphK1), sortilin failed to evoke endothelial impairment as well as NADPH oxidase activation. In endothelial cells, sortilin induced S1P-dependent activation of Rac1/NOX2 signaling axis, which was prevented by TY-52156, an antagonist of lysosphingolipid receptor S1P3. In vivo sortilin administration induced arterial hypertension in WT mice. In contrast, genetic deletion of S1P3 and gp91phox/NOX2 resulted in preservation of endothelial function and SBP unchanged levels after 14 days of systemic sortilin administration. Finally, to translate these research findings into a clinical setting, we found that hypertensive patients have higher plasma levels of sortilin, ASMase, S1P and soluble NOX2 derived peptide than normotensive subjects. Conclusions These results demonstrate the pathologic role of sortilin in the modulation of endothelial function and arterial blood pressure, suggesting that sortilin and its mediators might represent novel therapeutic targets in vascular diseases and hypertension. Funding Acknowledgement Type of funding source: None

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