Abstract MP14: Endothelial Mineralocorticoid Receptor Deletion Abrogates Leptin-induced Endothelial Dysfunction And Fetal Growth Restriction In Pregnant Mice

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Jessica L Faulkner ◽  
Derrian Wright ◽  
Simone Kennard ◽  
Galina Antonova ◽  
Iris Z Jaffe ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Fetal Growth ◽  
Repeated Measures ◽  
Mineralocorticoid Receptor ◽  
Vascular Inflammation ◽  
Fold Change ◽  
Pregnant Mice ◽  
Relaxation Responses ◽  
Plasma Leptin

Obesity increases preeclampsia (PE) risk. Plasma leptin levels increase with body weight in women with PE, and in addition, placental ischemia, an initiating event of PE, also increases plasma leptin. Our lab has shown that hyperleptinemia induces endothelial dysfunction and hypertension in female mice via endothelial mineralocorticoid receptor (ECMR) activation and that high progesterone levels of pregnancy increases ECMR expression. We hypothesized that leptin infusion induces PE-like endothelial dysfunction in pregnant mice, which is abrogated by ECMR deletion. Pregnant mice were infused with leptin by miniosmotic pump (0.9mg/kg/day, s.c.) on gestation day (GD) 11-18. Leptin decreased pup wt (0.86±0.04g ECMR +/+ vs 0.52±0.11 ECMR +/+ +leptin, *P<0.05). and increased fetal resorption (3±39% ECMR +/+ vs 42±32 ECMR +/+ +leptin, P=0.09). ECMR deletion rescued pup weight (0.91±0.06g ECMR -/- vs 1.0±0.07 ECMR -/- +leptin) and protected fetal resorptions (2±2% ECMR -/- vs 0±0 ECMR -/- +leptin) in leptin-infused pregnant mice. In association, placental efficiency (pup/placenta ratio) decreased with leptin in ECMR +/+ (9.7±0.7 ECMR +/+ vs 7.9±0.6 ECMR +/+ +leptin, *P<0.05), but not ECMR -/- (9.6±0.5 ECMR -/- vs 9.4±1.2 ECMR -/- +leptin) mice. Leptin infusion reduced endothelial function (acetylcholine-mediated relaxation) in aortas of ECMR +/+ , but not ECMR -/- , pregnant mice (2-way ANOVA, repeated measures, *P<0.05). Relaxation responses to acetylcholine with LNAME showed restoration of endothelial function in ECMR -/- +leptin mice was due to preserved NO bioavailability. No changes in endothelial-independent sodium nitroprusside or contractile responses to phenylephrine, serotonin or KCl were observed. ECMR deletion reduced aorta IL-1β mRNA (0.5±0.1-fold change ECMR +/+ +leptin vs 0.2±0.1-fold change ECMR -/- +leptin, P=0.06) levels and also placental growth factor mRNA (1.0±0.3-fold change ECMR +/+ +leptin vs 01.3±0.1 ECMR -/- +leptin, P=0.05) in placental tissues. Collectively, these data indicate that ECMR deletion protects pregnant mice from adverse fetal growth and demise in association with increasing NO vascular bioavailability, reducing vascular inflammation and improving placental function in a leptin-infused model of PE.

scholarly journals Selective deletion of endothelial mineralocorticoid receptor protects from vascular dysfunction in sodium-restricted female mice

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jessica L. Faulkner ◽  
Emily Lluch ◽  
Simone Kennard ◽  
Galina Antonova ◽  
Iris Z. Jaffe ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Mineralocorticoid Receptor ◽  
Vascular Reactivity ◽  
Vascular Dysfunction ◽  
Comorbid Condition ◽  
Female Mice ◽  
Vascular Contractility ◽  
Aldosterone Production ◽  
Relaxation Responses

Abstract Background Recent evidence by our laboratory demonstrates that women and female mice endogenously express higher endothelial mineralocorticoid receptor (ECMR) than males. Mounting clinical evidence also indicates that aldosterone production is higher in pathological conditions in females compared to males. However, the role for increased activation of ECMR by aldosterone in the absence of a comorbid condition is yet to be explored. The current study hypothesized that increased ECMR activation induced by elevated aldosterone production predisposes healthy female mice to endothelial dysfunction. Method Vascular reactivity was assessed in aortic rings from wild-type (WT) and ECMR KO (KO) mice fed either a normal salt (NSD, 0.4% NaCl) or sodium-restricted diet (SRD, 0.05% NaCl) for 28 days. Results SRD elevated plasma aldosterone levels as well as adrenal CYP11B2 and angiotensin II type 1 receptor (AT1R) expressions in female, but not male, WT mice. In baseline conditions (NSD), endothelial function, assessed by vascular relaxation to acetylcholine, was higher while vascular contractility to phenylephrine, serotonin, and KCl lower in female than male WT mice. SRD impaired endothelial function and increased vascular contractility in female, but not male, WT mice effectively ablating the baseline sex differences. NOS inhibition with LNAME ablated endothelial relaxation to a higher extent in male than female mice on NSD and ablated differences in acetylcholine relaxation responses between NSD- and SRD-fed females, indicating a role for NO in SRD-mediated endothelial function. In association, SRD significantly reduced vascular NOX4 expression in female, but not male, mice. Lastly, selective deletion of ECMR protected female mice from SRD-mediated endothelial dysfunction and increased vascular contractility. Conclusion Collectively, these data indicate that female mice develop aldosterone-induced endothelial dysfunction via endothelial MR-mediated reductions in NO bioavailability. In addition, these data support a role for ECMR to promote vascular contractility in female mice in response to sodium restriction.

scholarly journals Effect of spironolactone for 1 yr on endothelial function and vascular inflammation biomarkers in renal transplant recipients

2019 ◽  
Vol 317 (3) ◽  
pp. F529-F539 ◽  
Author(s):  
Line A. Mortensen ◽  
Claus Bistrup ◽  
Jane Stubbe ◽  
Mattias Carlström ◽  
Antonio Checa ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Renal Transplant ◽  
Endothelial Function ◽  
Adhesion Molecule ◽  
Mineralocorticoid Receptor ◽  
Vascular Inflammation ◽  
Treated Group ◽  
Transplant Patients ◽  
Mineralocorticoid Receptor Antagonism ◽  
Renal Transplant Patients

Kidney transplantation is associated with increased cardiovascular risk. Endothelial dysfunction and vascular inflammation contribute to negative outcome. In experimental models, mineralocorticoid receptor antagonists improved endothelial function and reduced inflammation. The present study tested the hypothesis that the mineralocorticoid receptor antagonist spironolactone improves endothelial function and reduces vascular inflammation in renal transplant patients. Eighty prevalent renal transplant patients from an ongoing, double-blind randomized placebo-controlled trial were included. Paired plasma samples before and after 1 yr of treatment ( n = 39 in the spironolactone-treated group and 41 in the placebo-treated group) were used to determine markers of endothelial dysfunction (nitrite, nitrate, cGMP, arginine, citrulline, ornithine, asymmetric dimethylarginine, symmetric dimethylarginine, NG-monomethyl-l-arginine, von Willebrand factor, tissue-type plasminogen activator antigen, and plasminogen activator inhibitor 1 antigen) and markers of inflammation (intercellular adhesion molecule, vascular adhesion molecule, high-sensitivity C-reactive protein, and serum amyloid protein A). The median time since the transplantation was 4.6 (0.12–22.3) yr in the spironolactone-treated group and 2.1 (0.17–13.9) yr in the placebo-treated group ( P > 0.05). Spironolactone increased plasma aldosterone ( P < 0.001) and K+ ( P < 0.001). Blood pressure did not change significantly. No significant differences were detected between groups in any of the measured markers of endothelial dysfunction or inflammation except in the subgroup analysis of patients with diabetes, where spironolactone decreased nitrite compared with placebo. In this study, mineralocorticoid receptor antagonism did not improve biomarkers of endothelial dysfunction or vascular inflammation in prevalent renal transplant patients. Further studies are needed to evaluate the potential beneficial effect of early or late mineralocorticoid receptor antagonism on vascular outcomes in renal transplant patients.

Abnormal endothelial vasomotor and secretory function

2015 ◽  
Author(s):  
Thimoteus Speer ◽  
Danilo Fliser
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Inflammation ◽  
Secretory Function ◽  
Vascular Integrity ◽  
Non Invasive ◽  
Other Substances ◽  
Modified Lipoproteins ◽  
And Function

The endothelium plays a crucial role in the maintenance of vascular integrity and function. Nitric oxide produced by endothelial cells is a key player, inducing relaxation of vascular smooth muscle cells, inhibition of vascular inflammation, and prevention of coagulatory activation. Chronic kidney disease (CKD) is characterized by deterioration of different protective endothelial properties, collectively described as endothelial dysfunction. Several factors such as methylarginines, modified lipoproteins, and other substances that accumulate may be involved in the pathogenesis of endothelial dysfunction of CKD. Endothelial dysfunction is suggested to be the first critical step in the initiation of atherosclerosis. Clinical assessment of endothelial function may become important in recognition of patients with increased cardiovascular risk. Beside several invasive and non-invasive methods to assess endothelial function in vivo, measurement of circulating (bio)markers may be useful for the evaluation of endothelial dysfunction.

scholarly journals Activation of Yes-Associated Protein/PDZ-Binding Motif Pathway Contributes to Endothelial Dysfunction and Vascular Inflammation in AngiotensinII Hypertension

2021 ◽  
Vol 12 ◽  
Author(s):  
Qian Xu ◽  
Kunping Zhuo ◽  
Ruiping Cai ◽  
Xiaomin Su ◽  
Lu Zhang ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Umbilical Vein ◽  
Vascular Inflammation ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Umbilical Vein Endothelial Cells

Yes-associated protein (YAP) and its associated coactivator of PDZ-binding motif (TAZ) are co-transcriptional regulators and down effectors of the Hippo signaling pathway. Recent studies have shown that the Hippo/YAP signaling pathway may play a role in mediating vascular homeostasis. This study investigated the role of YAP/TAZ in endothelial dysfunction and vascular inflammation in angiotensin (Ang)II hypertensive mice. The infusion of AngII (1.1 mg/kg/day by mini-pump) for 3 weeks induced the activation of YAP/TAZ, manifested by decreased cytosolic phosphor-YAP and phosphor-TAZ, and increased YAP/TAZ nuclear translocation, which were prevented by YAP/TAZ inhibitor verteporfin. AngII significantly increased systolic blood pressure (SBP), macrophage infiltration, and expressions of proinflammatory cytokines, and impaired endothelial function in the aorta of the mice. Treatment with verteporfin improved endothelial function and reduced vascular inflammation with a mild reduction in SBP. AngII also induced YAP/TAZ activation in human umbilical vein endothelial cells in vitro, which were prevented by LB-100, an inhibitor of protein phosphatase 2A (PP2A, a major dephosphorylase). Treatment with LB-100 reversed AngII-induced proinflammatory cytokine expression and impairment of phosphor-eNOS expression in vitro. Our results suggest that AngII induces YAP/TAZ activation via PP2A-dependent dephosphorylation, which may contribute to the impairment of endothelial function and the induction of vascular inflammation in hypertension. YAP/TAZ may be a new target for hypertensive vascular injury.

Abstract 3429: Amlodipine Improves Endothelial Function and Metabolic Parameters in Patients with Hypertension

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Kwang K Koh ◽  
Michael J Quon ◽  
Seung H Han ◽  
Wook-Jin Chung
Keyword(s):  
Blood Pressure ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Hdl Cholesterol ◽  
Multivariate Regression Analysis ◽  
Metabolic Parameters ◽  
Double Blind ◽  
Reciprocal Relationships ◽  
Plasma Leptin ◽  
Plasma Malondialdehyde

Background : Reciprocal relationships between endothelial dysfunction and insulin resistance imply that improvement in endothelial dysfunction will have beneficial metabolic consequences. We hypothesized that amlodipine therapy will improve endothelial dysfunction and metabolic parameters in hypertensive subjects. Methods : Amlodipine (10 mg daily for 8 weeks) or placebo was given to each 45 patients with mild to moderate hypertension in a randomized, double-blind, placebo-controlled, and paralleled study. Age, sex, and body mass index were matched. Results : Amlodipine therapy significantly reduced systolic and diastolic blood pressure and increased HDL-cholesterol to greater extent than placebo therapy (all P< 0.001). Amlodipine therapy significantly improved flow-mediated dilator response to hyperemia and reduced plasma malondialdehyde levels to greater extent than placebo therapy ( P< 0.001 and P =0.035). Amlodipine therapy significantly increased plasma adiponectin levels ( P =0.009) and decreased plasma leptin and resistin levels ( P< 0.001 and P =0.025, respectively) to greater extent than placebo therapy. Correlations were noted between percent changes in adiponectin levels and percent changes in HDL-cholesterol ( r =0.348, P =0.019) and QUICKI ( r =0.326, P =0.029) following amlodipine therapy. Only changes in HDL-cholesterol (β = 0.469, P = 0.019) and QUICKI (β = 1.786, P = 0.069) were independent predictors of changes in adiponectin levels (multivariate regression analysis). We also observed inverse correlations between percent changes in leptin levels and percent changes in QUICKI ( r = −0.569, P< 0.001) following amlodipine therapy with changes in QUICKI (β = 1.810, P < 0.001) as an independent predictor of changes in leptin levels. Conclusions : Amlodipine therapy improves blood pressure, endothelial function, and metabolic parameters in patients with hypertension.

Abstract 03: Ablation Of Endothelial Dysfunction Improves Blood Pressure And Fetal Growth Restriction In A Mouse Model Of Preeclampsia-like Hyperleptinemia

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Jessica L Faulkner ◽  
Derrian Wright ◽  
Simone Kennard ◽  
Galina Antonova ◽  
Iris Z Jaffe ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Fold Change ◽  
Growth Restriction ◽  
Mesenteric Arteries ◽  
Pregnant Mice ◽  
Placental Efficiency

Placental ischemia, an initiating event of preeclampsia (PE), increases plasma leptin levels. We recently developed a model of midgestation (gestation day (GD)11-18) leptin infusion mimicking the midgestation rise in leptin levels of PE patients. Our previous work demonstrates that deletion of endothelial mineralocorticoid receptors (ECMR) improves markers of vascular dysfunction in leptin-infused female mice. We hypothesized vascular function improvement with ECMR deletion ablates hypertension and fetal growth restriction in pregnant leptin-infused mice. Pregnant ECMR +/+ (WT) and ECMR -/- (KO) mice were infused with vehicle or leptin by osmotic pump (lep, 0.9mg/kg/day, s.c.) on GD11-18 while implanted with radiotelemeters for conscious blood pressure (BP) measurement and wire myography of thoracic aorta and 2 nd order mesenteric arteries at GD18 (*=P<0.05). Leptin infusion did not decrease maternal weight in any groups. Leptin decreased pup weight (0.86±0.04g WT vs 0.52±0.11 WT+lep*) and placental efficiency (pup/placenta ratio) (9.7±0.7 WT vs 7.9±0.6 WT+lep*) in WT pregnant mice. ECMR deletion prevented leptin-mediated decreases in pup weight (0.91±0.06g KO vs 1.0±0.07 KO+lep) and placental efficiency (9.6±0.5 KO vs 9.4±1.2 KO+lep). Mean arterial pressure (BP) increased in leptin-infused WT (102±3mmHg WT vs 120±12 WT+lep*), but not KO (107±2 KO vs 106±8 KO+lep), mice from GD11-18. Leptin infusion reduced acetylcholine-mediated relaxation in both aorta and mesenteric arteries of WT* and constriction to KCl in mesenteric arteries in WT*, but not KO, pregnant mice (2-way ANOVA, repeated measures). Leptin increased plasma endothelin-1 (ET-1, 1.1±0.3 pg/ml WT vs 4.4±1.8 WT+lep*), placental mRNA expression of prepro-ET-1 (1.9±0.3-fold change from WT*) and ET-1 converting enzyme-1 (1.6±0.3-fold change from WT*) in pregnant WT mice. Leptin infusion also increased adrenal aldosterone-synthase protein (1.4±0.4 WT ratio/β actin vs 3.2±0.3 WT+lep*) and angiotensin II type 1 receptor b (3.5±0.8-fold change from WT*) mRNA in pregnant mice. Collectively, these data indicate that leptin infusion induces hypertension and fetal growth restriction in pregnant mice due to vascular dysfunction and increased ECMR activation in pregnant mice.

scholarly journals Effect of Different Classes of Antihypertensive Drugs on Endothelial Function and Inflammation

2019 ◽  
Vol 20 (14) ◽  
pp. 3458 ◽  
Author(s):  
Isabella Viana Gomes Silva ◽  
Roberta Carvalho de Figueiredo ◽  
Danyelle Romana Alves Rios
Keyword(s):  
Cardiovascular Diseases ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Antihypertensive Drugs ◽  
Vascular Inflammation ◽  
Functional Changes ◽  
Beneficial Effects ◽  
Reactive Protein ◽  
Pressure Lowering ◽  
Effect Of Treatment

Hypertension is characterized by structural and functional changes in blood vessels that travel with increased arterial stiffness, vascular inflammation, and endothelial dysfunction. Some antihypertensive drugs have been shown to improve endothelial function and reduce levels of inflammatory markers regardless of the effect of blood pressure lowering. Third-generation β-blockers, such as nebivolol and carvedilol, because they have additional properties, have been shown to improve endothelial function in patients with hypertension. Calcium channel antagonists, because they have antioxidant effects, may improve endothelial function and vascular inflammation.The Angiotensin Receptor Blocker (ARBs) are able to improve endothelial dysfunction and vascular inflammation in patients with hypertension and other cardiovascular diseases. Angiotensin converting enzyme (ACE) inhibitors have shown beneficial effects on endothelial function in patients with hypertension and other cardiovascular diseases, however there are few studies evaluating the effect of treatment with this class on the reduction of C-reactive protein (CRP) levels. Further studies are needed to assess whether treatment of endothelial dysfunction and vascular inflammation may improve the prognosis of patients with essential hypertension.

Endothelial Mineralocorticoid Receptor Deletion Abrogates Leptin‐Induced Endothelial Dysfunction in Pregnant Mice

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Jessica L. Faulkner ◽  
Derrian Wright ◽  
Simone Kennard ◽  
Galina Antonova ◽  
Iris Jaffe ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Mineralocorticoid Receptor ◽  
Pregnant Mice

scholarly journals Endothelial mineralocorticoid receptor deletion ablates leptin‐induced cardiovascular and fetal growth preeclampsia characteristics in pregnant mice

2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Jessica Faulkner ◽  
Derrian Wright ◽  
Simone Kennard ◽  
Galina Antonova ◽  
Iris Jaffe ◽  
...  
Keyword(s):  
Fetal Growth ◽  
Mineralocorticoid Receptor ◽  
Pregnant Mice

scholarly journals Hepatocyte-derived exosomal microRNAs orchestrate vascular inflammation and endothelial function: insights into molecular mechanisms of trimethylamine-N-Oxide in atherosclerosis

2021 ◽  
Author(s):  
Xiang Liu ◽  
Yijia Shao ◽  
Jiazichao Tu ◽  
Jiapan Sun ◽  
Lifu Li ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Vascular Inflammation ◽  
Signal Pathways ◽  
Physiological Concentration ◽  
Aortic Endothelial Cells ◽  
Sequencing Strategy

Abstract Background: Trimethylamine-N-oxide (TMAO) has been proved to be a new proatherogenic compound for promoting vascular inflammation and endothelial dysfunction. Hepatocyte-derived exosomes played an important role in the regulation of vascular inflammation and endothelial function. Since TMAO is produced in the liver, hepatocytes may be the first potential target of TMAO. However, it is not clear whether TMAO can directly stimulate normal hepatocytes to produce exosomes so as to mediate the motivating effects of TMAO on inflammation and endothelial dysfunction.Methods: The hepatocytes were cultured and treated with TMAO at a physiological concentration for 24 hours (TMAO-Exos). The untreated group served as the control (Control-Exos). The exosomes were isolated from the culture supernatant and then added to the human aortic endothelial cells (HAECs) for 48 hours. The mRNA expressions of inflammatory cytokines and caspase-3 were determined by qPCR and cell apoptosis was evaluated by using the Hoechst 33342 staining solution. The miRNA profile in the exosomes were detected using an RNA-sequencing strategy. The miRNA-mRNA network was predicted, and the biological functions of the target genes were annotated by using bioinformatics methods.Results: TMAO-Exos were able to promote the expressions of inflammatory cytokines and HAECs apoptosis. Moreover, miRNAs carried by the TMAO-Exos were quite different from that in the Control-Exos, including miR-92a-3p, miR-103-3p and miR-122-5p, etc. Further analysis showed that these differentially expressed miRNAs were predicted to target genes such as Mapk8, Casp9, Mapk10, Bcl2l11, Ikbkg and Akt1, which were supposed to be involved in the signal pathways related to vascular inflammation and endothelial function.Conclusions: These novel results provided evidence that TMAO could indirectly talk to vascular endothelial via promoting hepatocytes to secreting exosomes that carried important genetic information, which may give a new insight into the interactions between liver and vasculature in the atherogenesis caused by TMAO. New intervention targeting this cellular crosstalk may be feasible and effective in the prevention and treatment of TMAO-induced atherogenesis.

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