Differential effects of obesity on visceral vs. subcutaneous adipose arteries: role of shear activated Kir2.1 and alterations to the glycocalyx

2021 ◽  
Author(s):  
Sang Joon Ahn ◽  
Elizabeth Le Master ◽  
James C. Lee ◽  
Shane A. Phillips ◽  
Irena Levitan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Ex Vivo ◽  
Flow Chamber ◽  
Dominant Negative ◽  
Obese Mice ◽  
Shear Sensitivity ◽  
Electrophysiological Recordings ◽  
Subcutaneous Adipose

Obesity imposes well-established deficits to endothelial function. We recently showed that obesity-induced endothelial dysfunction was mediated by disruption of the glycocalyx and a loss of Kir channel flow-sensitivity. However, obesity-induced endothelial dysfunction is not observed in all vascular beds: visceral adipose arteries (VAA), but not subcutaneous adipose arteries (SAA), exhibit endothelial dysfunction. Aim: To determine if differences in SAA vs. VAA endothelial function observed in obesity are attributed to differential impairment of Kir channels and alterations to the glycocalyx. Methods: Mice were fed a normal rodent diet, or a high fat Western diet to induce obesity. Flow-induced vasodilation (FIV) was measured ex vivo. Functional downregulation of endothelial Kir2.1 was accomplished by transducing adipose arteries from mice and obese humans with adenovirus containing a dominant-negative Kir2.1 construct. Kir function was tested in freshly isolated endothelial cells seeded in a flow chamber for electrophysiological recordings under fluid shear. Atomic force microscopy was used to assess biophysical properties of the glycocalyx. Results: Endothelial dysfunction was observed in VAA of obese mice and humans. Downregulating Kir2.1 blunted FIV in SAA, but had no effect on VAA, from obese mice and humans. Obesity abolished Kir shear-sensitivity in VAA endothelial cells and significantly altered the VAA glycocalyx. In contrast, Kir shear-sensitivity was observed in SAA endothelial cells from obese mice and effects on SAA glycocalyx were less pronounced. Conclusions: We reveal distinct differences in Kir function and alterations to the glycocalyx that we propose contribute to the dichotomy in SAA vs. VAA endothelial function with obesity.

Abstract 14050: The Gut Flora Promotes Endothelial Dysfunction Through Vascular MicroRNA-204-mediated Down-regulation of Endothelial Sirtuin1

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Ajit Vikram ◽  
Young-Rae Kim ◽  
Santosh Kumar ◽  
Julia S Jacobs ◽  
Kaikobad Irani
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
High Fat Diet ◽  
Ex Vivo ◽  
Vascular Wall ◽  
High Fat ◽  
Gut Flora ◽  
Atherosclerotic Vascular Disease ◽  
Germ Free

The gut flora contributes to development of atherosclerosis. Endothelial dysfunction, one manifestation of which is impaired endothelium-dependent vasorelaxation, accompanies and promotes atherosclerotic vascular disease. Here we show that gut flora impair endothelium-dependent vasorelaxation by remotely up-regulating microRNA-204 (miR-204) which downregulates SIRTUIN1 (SIRT1) in the vascular wall. Microarray analysis in aortas of germ-free mice revealed a set of down-regulated microRNAs, including miR-204, which target SIRT1. Suppression of gut flora in mice with antibiotics in drinking water decreased aortic miR-204, increased aortic SIRT1, and improved endothelium-dependent vasorelaxation, effects that were reversed with discontinuation of antibiotics. In addition, miR-204 mimic impaired endothelium-dependent aortic vasorelaxation ex vivo. Moreover, high-fat diet feeding stimulated aortic miR-204, suppressed SIRT1, and impaired endothelial function, all of which were mitigated by administration of antibiotics, and reversed with stoppage of antibiotics. In contrast, antibiotics did not improve high-fat diet-induced endothelial dysfunction in mice conditionally lacking endothelial SIRT1. In addition, anti-miR-204 delivered systemically prevented high-fat diet-induced endothelial dysfunction and vascular SIRT1 decrease. Finally, serum from mice on antibiotics suppressed miR-204, and increased SIRT1, in endothelial cells, effects that were not observed with serum from mice in which antibiotics were discontinued. Therefore, the gut flora remotely downregulates endothelial SIRT1 through miR-204, leading to impairment of endothelial function.

scholarly journals Irisin Regulates Heme Oxygenase-1/Adiponectin Axis in Perivascular Adipose Tissue and Improves Endothelial Dysfunction in Diet-Induced Obese Mice

2017 ◽  
Vol 42 (2) ◽  
pp. 603-614 ◽  
Author(s):  
Ningning Hou ◽  
Gang Du ◽  
Fang Han ◽  
Jin Zhang ◽  
Xiaotong Jiao ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Heme Oxygenase ◽  
Ex Vivo ◽  
Heme Oxygenase 1 ◽  
No Production ◽  
Obese Mice ◽  
Perivascular Adipose Tissue ◽  
Tnf Α

Aims: To determine whether irisin could improve endothelial dysfunction by regulating heme oxygenase-1(HO-1)/adiponectin axis in perivascular adipose tissue (PVAT) in obesity. Methods: Male C57BL/6 mice were fed with a high-fat diet (HFD) with or without irisin treatment. Endothelium-dependent vasorelaxation of the thoracic aorta with or without PVAT (PVAT+ or PVAT–) was determined. Western blot was employed to determine the levels of HO-1 and adiponectin in PVAT. UCP-1, Cidea, and TNF-α gene expression in PVAT were tested by real-time PCR. Results: The presence of PVAT significantly impaired endothelial function in the HFD mice. Treatment of HFD mice with irisin significantly restored this impairment and improved endothelial function in vivo or ex vivo. Incubated aortic rings (PVAT-) with PVAT-derived conditioned medium (CM) from HFD mice impaired endothelial function in control mice. This impairment was prevented by incubating the aortic rings (PVAT-) from HFD mice with PVAT-derived CM from irisin. However, the beneficial effects were partly attenuated in the presence of HO-1 inhibitor and adiponectin receptor blocking peptide. Treatment of HFD mice with irisin significantly increased NO production, protein levels of HO-1 and adiponectin, mRNA expressions of UCP-1 and Cidea, and decreased superoxide production and TNF-α expression in PVAT. Conclusion: Irisin improved endothelial function by modulating HO-1/ adiponectin axis in PVAT in HFD-induced obese mice. These findings suggest that regulating PVAT function may be a potential mechanism by which irisin improves endothelial function in obesity.

scholarly journals Downregulation of Erythrocyte miR-210 Induces Endothelial Dysfunction in Type 2 Diabetes

2021 ◽  
Author(s):  
Zhichao Zhou ◽  
Aida Collado ◽  
Changyan Sun ◽  
Yahor Tratsiakovich ◽  
Ali Mahdi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Ex Vivo ◽  
Tyrosine Phosphatase ◽  
Protective Role ◽  
Diabetic Patients

Red blood cells (RBCs) act as mediators of vascular injury in type 2 diabetes mellitus (T2DM). miR-210 plays a protective role in cardiovascular homeostasis and is decreased in whole blood of T2DM mice. We hypothesized that downregulation of RBC miR-210 induces endothelial dysfunction in T2DM. RBCs were co-incubated with arteries and endothelial cells <i>ex vivo</i> and transfused <i>in vivo</i> to identify the role of miR-210 and its target protein tyrosine phosphatase 1B (PTP1B) in endothelial dysfunction. RBCs from patients with T2DM (T2DM RBC) and diabetic rodents induced endothelial dysfunction <i>ex vivo</i> and <i>in vivo</i>. miR-210 levels were lower in human T2DM RBC than in RBCs from healthy subjects (H RBC). Transfection of miR-210 in human T2DM RBC rescued endothelial function, whereas miR-210 inhibition in H RBC or RBCs from miR-210 knockout mice impaired endothelial function. Human T2DM RBC decreased miR-210 expression in endothelial cells. miR-210 expression in carotid artery plaques was lower in T2DM patients than in non-diabetic patients. Endothelial dysfunction induced by downregulated RBC miR-210 involved PTP1B and reactive oxygen species. miR-210 mimic attenuated endothelial dysfunction induced by RBCs via downregulating vascular PTP1B and oxidative stress in diabetic mice <i>in vivo</i>. These data reveal that the downregulation of RBC miR-210 is a novel mechanism driving the development of endothelial dysfunction in T2DM.

scholarly journals Endothelial Dysfunction in Fabry Disease Is Related to Glycocalyx Degradation

2021 ◽  
Vol 12 ◽  
Author(s):  
Solvey Pollmann ◽  
David Scharnetzki ◽  
Dominique Manikowski ◽  
Malte Lenders ◽  
Eva Brand
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Fabry Disease ◽  
Specific Inhibitor ◽  
Small Vessel ◽  
Endothelial Glycocalyx ◽  
Enzyme Replacement ◽  
Anti Inflammatory

Fabry disease (FD) is an X-linked multisystemic lysosomal storage disease due to a deficiency of α-galactosidase A (GLA/AGAL). Progressive cellular accumulation of the AGAL substrate globotriaosylceramide (Gb3) leads to endothelial dysfunction. Here, we analyzed endothelial function in vivo and in vitro in an AGAL-deficient genetic background to identify the processes underlying this small vessel disease. Arterial stiffness and endothelial function was prospectively measured in five males carrying GLA variants (control) and 22 FD patients under therapy. AGAL-deficient endothelial cells (EA.hy926) and monocytes (THP1) were used to analyze endothelial glycocalyx structure, function, and underlying inflammatory signals. Glycocalyx thickness and small vessel function improved significantly over time (p&lt;0.05) in patients treated with enzyme replacement therapy (ERT, n=16) and chaperones (n=6). AGAL-deficient endothelial cells showed reduced glycocalyx and increased monocyte adhesion (p&lt;0.05). In addition, increased expression of angiopoietin-2, heparanase and NF-κB was detected (all p&lt;0.05). Incubation of wild-type endothelial cells with pathological globotriaosylsphingosine concentrations resulted in comparable findings. Treatment of AGAL-deficient cells with recombinant AGAL (p&lt;0.01), heparin (p&lt;0.01), anti-inflammatory (p&lt;0.001) and antioxidant drugs (p&lt;0.05), and a specific inhibitor (razuprotafib) of angiopoietin-1 receptor (Tie2) (p&lt;0.05) improved glycocalyx structure and endothelial function in vitro. We conclude that chronic inflammation, including the release of heparanases, appears to be responsible for the degradation of the endothelial glycocalyx and may explain the endothelial dysfunction in FD. This process is partially reversible by FD-specific and anti-inflammatory treatment, such as targeted protective Tie2 treatment.

scholarly journals O-GlcNAcase overexpression reverses coronary endothelial cell dysfunction in type 1 diabetic mice

2015 ◽  
Vol 309 (9) ◽  
pp. C593-C599 ◽  
Author(s):  
Ayako Makino ◽  
Anzhi Dai ◽  
Ying Han ◽  
Katia D. Youssef ◽  
Weihua Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Protein Modification ◽  
Control Level ◽  
Vascular Complications ◽  
Capillary Density ◽  
Diabetic Mice ◽  
Endothelium Dependent Relaxation

Cardiovascular disease is the primary cause of morbidity and mortality in diabetes, and endothelial dysfunction is commonly seen in these patients. Increased O-linked N-acetylglucosamine ( O-GlcNAc) protein modification is one of the central pathogenic features of diabetes. Modification of proteins by O-GlcNAc ( O-GlcNAcylation) is regulated by two key enzymes: β- N-acetylglucosaminidase [ O-GlcNAcase (OGA)], which catalyzes the reduction of protein O-GlcNAcylation, and O-GlcNAc transferase (OGT), which induces O-GlcNAcylation. However, it is not known whether reducing O-GlcNAcylation can improve endothelial dysfunction in diabetes. To examine the effect of endothelium-specific OGA overexpression on protein O-GlcNAcylation and coronary endothelial function in diabetic mice, we generated tetracycline-inducible, endothelium-specific OGA transgenic mice, and induced OGA by doxycycline administration in streptozotocin-induced type 1 diabetic mice. OGA protein expression was significantly decreased in mouse coronary endothelial cells (MCECs) isolated from diabetic mice compared with control MCECs, whereas OGT protein level was markedly increased. The level of protein O-GlcNAcylation was increased in diabetic compared with control mice, and OGA overexpression significantly decreased the level of protein O-GlcNAcylation in MCECs from diabetic mice. Capillary density in the left ventricle and endothelium-dependent relaxation in coronary arteries were significantly decreased in diabetes, while OGA overexpression increased capillary density to the control level and restored endothelium-dependent relaxation without changing endothelium-independent relaxation. We found that connexin 40 could be the potential target of O-GlcNAcylation that regulates the endothelial functions in diabetes. These data suggest that OGA overexpression in endothelial cells improves endothelial function and may have a beneficial effect on coronary vascular complications in diabetes.

scholarly journals Hydroxytyrosol Ameliorates Endothelial Function under Inflammatory Conditions by Preventing Mitochondrial Dysfunction

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Nadia Calabriso ◽  
Antonio Gnoni ◽  
Eleonora Stanca ◽  
Alessandro Cavallo ◽  
Fabrizio Damiano ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Mitochondrial Function ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Inflamed Endothelium

Mitochondria are fundamental organelles producing energy and reactive oxygen species (ROS); their impaired functions play a key role in endothelial dysfunction. Hydroxytyrosol (HT), a well-known olive oil antioxidant, exerts health benefits against vascular diseases by improving endothelial function. However, the HT role in mitochondrial oxidative stress in endothelial dysfunction is not clear yet. To investigate the HT effects on mitochondrial ROS production in the inflamed endothelium, we used an in vitro model of endothelial dysfunction represented by cultured endothelial cells, challenged with phorbol myristate acetate (PMA), an inflammatory, prooxidant, and proangiogenic agent. We found that the pretreatment of endothelial cells with HT (1–30 μmol/L) suppressed inflammatory angiogenesis, a crucial aspect of endothelial dysfunction. The HT inhibitory effect is related to reduced mitochondrial superoxide production and lipid peroxidation and to increased superoxide dismutase activity. HT, in a concentration-dependent manner, improved endothelial mitochondrial function by reverting the PMA-induced reduction of mitochondrial membrane potential, ATP synthesis, and ATP5β expression. In PMA-challenged endothelial cells, HT also promoted mitochondrial biogenesis through increased mitochondrial DNA content and expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, nuclear respiratory factor-1, and mitochondrial transcription factor A. These results highlight that HT blunts endothelial dysfunction and pathological angiogenesis by ameliorating mitochondrial function, thus suggesting HT as a potential mitochondria-targeting antioxidant in the inflamed endothelium.

scholarly journals Dynamics of endothelian function in different treatment strategies in stable ischemic heart disease

2019 ◽  
Vol 11 (1) ◽  
pp. 5-12
Author(s):  
Sergey A. Sayganov ◽  
Anastasiia M. Kuzmina-Krutetskaia
Keyword(s):  
Endothelial Cells ◽  
Heart Disease ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Ischemic Heart Disease ◽  
Peripheral Blood ◽  
Ischemic Heart ◽  
Circulating Endothelial Cells ◽  
Lipid Lowering ◽  
Stable Ischemic Heart Disease

Aim. To assess the dynamics of endothelial function by determining circulating endothelial cells in peripheral blood in patients with stable ischemic heart disease within various treatment approaches. Material and methods. The study involved 98 patients with stable ischemic heart disease and 30 patients in the control group without coronary atherosclerosis. Endothelial function was assessed by determining the number of circulating endothelial cells in peripheral blood using flow cytofluorimetry with antibodies to cell surface markers: CD146+CD45– at the baseline. Depending on the treatment tactics, the study participants were divided into 3 groups: the medicamental therapy group, the group of coronary stenting, and the group of coronary bypass surgery. After 3 months from the baseline, dinamics assessment of endothelial dysfunction was performed. Results. Endothelial dysfunction was observed in all patients with obstructive lesions of the coronary blood flow and associated with effort angina class and anatomical severity of coronary disease. Improvement of endothelial function was facilitated by lipid-lowering therapy. Revascularization by coronary stenting impaired endothelial function in three months after the intervention. Mycoardial revascularization by coronary bypass did not impair endothelial function. Conclusion. Examination of endothelial dysfunction by determining the number of circulating endothelial cells in peripheral blood can be used to assess the severity of endothelial dysfunction in patients with IHD receiving lipid-lowering therapy and undergoing surgical revascularization.

scholarly journals FGF23 impairs peripheral microvascular function in renal failure

2018 ◽  
Vol 315 (5) ◽  
pp. H1414-H1424 ◽  
Author(s):  
Melissa Verkaik ◽  
Rio P. Juni ◽  
Ellen P. M. van Loon ◽  
Erik M. van Poelgeest ◽  
Rick F. J. Kwekkeboom ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Endothelial Dysfunction ◽  
Kidney Disease ◽  
Asymmetric Dimethylarginine ◽  
Ex Vivo ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth

Cardiovascular diseases account for ~50% of mortality in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) is independently associated with endothelial dysfunction and cardiovascular mortality. We hypothesized that CKD impairs microvascular endothelial function and that this can be attributed to FGF23. Mice were subjected to partial nephrectomy (5/6Nx) or sham surgery. To evaluate the functional role of FGF23, non-CKD mice received FGF23 injections and CKD mice received FGF23-blocking antibodies after 5/6Nx surgery. To examine microvascular function, myocardial perfusion in vivo and vascular function of gracilis resistance arteries ex vivo were assessed in mice. 5/6Nx surgery blunted ex vivo vasodilator responses to acetylcholine, whereas responses to sodium nitroprusside or endothelin were normal. In vivo FGF23 injections in non-CKD mice mimicked this endothelial defect, and FGF23 antibodies in 5/6Nx mice prevented endothelial dysfunction. Stimulation of microvascular endothelial cells with FGF23 in vitro did not induce ERK phosphorylation. Increased plasma asymmetric dimethylarginine concentrations were increased by FGF23 and strongly correlated with endothelial dysfunction. Increased FGF23 concentration did not mimic impaired endothelial function in the myocardium of 5/6Nx mice. In conclusion, impaired peripheral endothelium-dependent vasodilatation in 5/6Nx mice is mediated by FGF23 and can be prevented by blocking FGF23. These data corroborate FGF23 as an important target to combat cardiovascular disease in CKD.NEW & NOTEWORTHY In the present study, we provide the first evidence that fibroblast growth factor 23 (FGF23) is a cause of peripheral endothelial dysfunction in a model of early chronic kidney disease (CKD) and that endothelial dysfunction in CKD can be prevented by blockade of FGF23. This pathological effect on endothelial cells was induced by long-term exposure of physiological levels of FGF23. Mechanistically, increased plasma asymmetric dimethylarginine concentrations were strongly associated with this endothelial dysfunction in CKD and were increased by FGF23.

Cocaine-Induced Endothelial Dysfunction: Role of RhoA/Rho Kinase Pathway Activation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2177-2177
Author(s):  
Jaime Pereira ◽  
Claudia G Saez ◽  
Julio Pallavicini ◽  
Karla Pereira-Flores ◽  
Camila Mendoza ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Kinase Activity ◽  
Ex Vivo ◽  
Rho Kinase ◽  
Chronic Cocaine ◽  
Cocaine Users ◽  
Rock Activity

Abstract Abstract 2177 Background. Cocaine abuse is associated with an increased risk of cardiac and cerebrovascular events, such as myocardial infarction, sudden cardiac death, and ischemic stroke. The underlying mechanisms leading to these complications are not fully understood although intravascular thrombus formation and accelerated atherosclerosis are prominent findings. We have recently demonstrated that chronic cocaine use is associated with endothelial dysfunction (Sáez et al. Thromb Res 2011; 128: 18), a key event in the onset and progression of atherosclerosis. There is growing evidence that the RhoA/Rho kinase (ROCK) pathway has an important pathophysiological role in vascular endothelial dysfunction. Accordingly, we hypothesized that cocaine use induces activation of RhoA/ROCK pathway. Objectives. The main aim of this work was to investigate the activation of RhoA/ROCK pathway through ex vivo, in vivo and in vitro studies. Methods. Ex vivo studies. We studied 13 cocaine dependent individuals (aged 19–52 years mean age 37 years) who met DSM-IV criteria for cocaine dependence, seeking treatment for cocaine abuse and age, sex-matched healthy controls (aged 20–49 years, mean age 35 years). Samples were obtained at admission, within 72 hours of drug exposure. Endothelial cell damage was determined by enumerating circulating endothelial cells (CECs). Rho-kinase activity was assessed by the levels of phosphorylated to total myosin light chain phosphatase 1 (MYPT1-P/T) in circulating leukocytes. In vivo studies. Adult male Sprague-Dawley rats were randomly assigned to receive either cocaine (30mg/kg, provided by NIDA, USA) or saline intraperitoneally once daily for 21 days. The levels of aortic phosphorylated MYPT1 (phospho-MYPT1) were assessed by western blot in aorta extracts. In vitro experiments. Human umbilical vein endothelial cells (HUVECs) were cultured under standard conditions and supplemented for 5 hours with plasma from chronic cocaine users, normal plasma, cocaine (10μM) or vehicle. After media removal, HUVECs were either lysed for determination of ROCK activity or co-cultured with resting platelets and immunostained for von Willebrand factor (FVW). Platelet adhesion was evaluated by immunofluorescence microsocopy. Experiments were conducted in the presence or absence of ROCK inhibitors, Y-27632 (10 μM) or atorvastatin (10μM). Results. Cocaine users showed significantly elevated number of CECs compared to the controls (65 ± 6.6 vs 14 ± 3.4 cells/mL, p: 0.0002). In the control subjects, leukocyte mean MYPT1-P/T ratio was 2.2 ± 0.8 whereas in cocaine addicts were significantly increased (9.8 ± 2.8; p 0.015). ROCK activity was higher by 100% (p: 0.019) in the aortic wall of the cocaine-treated rats compared to sham animals. HUVECs supplemented with plasma from cocaine users showed an increase in ROCK activity by 25% (p: 0.039), released significantly higher amount of FVW (p<0.05) and adhered a larger number of platelets (22.6±5 vs 7.9±3 platelets/cell, respectively; p: 0.006) compared with control plasma. Cocaine exposure induced a dramatically higher number of platelets adhered to HUVEC than in vehicle-treated cells (220±73 vs 10.2±1.1 platelets/cell, respectively; p>0.001).ROCK inhibitors, atorvastatin and Y-27632 reduced the release of FVW by HUVECs exposed to plasma from cocaine users by 65% (p: 0.004) and strongly inhibited platelet adhesion (by 75% in plasma-treated cells and by 90% in HUVECs exposed to cocaine, p:< 0.006). Conclusions. We found an increase in Rho kinase activity in peripheral leukocytes of cocaine abusers, in the vessel wall of rats exposed to cocaine and a marked positive effect of ROCK inhibitors on the cellular injury induced by cocaine or plasma from cocaine consumers on endothelial cells. Collectively, these data suggest that activation of RhoA/ROCK pathway plays a key role in cocaine-induced endothelial dysfunction. Inhibition of ROCK may provide therapeutic benefits in a comprehensive treatment for cocaine addiction. Disclosures: No relevant conflicts of interest to declare.

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