Glycyrrhetinic acid attenuates vascular smooth muscle vasodilatory function in healthy humans

2010 ◽  
Vol 119 (10) ◽  
pp. 437-442 ◽  
Author(s):  
Piotr Sobieszczyk ◽  
Barry A. Borlaug ◽  
Heather L. Gornik ◽  
Wesley D. Knauft ◽  
Joshua A. Beckman
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Vascular Function ◽  
Glucocorticoid Receptors ◽  
Vascular Dysfunction ◽  
Glycyrrhetinic Acid ◽  
Urinary Cortisol ◽  
Healthy Humans ◽  
Vasodilatory Function ◽  
Double Blinded

Abnormal glucocorticoid metabolism contributes to vascular dysfunction and cardiovascular disease. Cortisol activation of vascular mineralocorticoid and glucocorticoid receptors is regulated by two types of 11β-HSD (11-β hydroxysteroid dehydrogenase), namely 11β-HSD2 and 11β-HSD1 (type 2 and type 1 11β-HSD respectively). We hypothesized that inhibition of 11β-HSD would attenuate vascular function in healthy humans. A total of 15 healthy subjects were treated with the selective 11β-HSD inhibitor GA (glycyrrhetinic acid) or matching placebo in a randomized double-blinded cross-over trial. 11β-HSD activity was assessed by the urinary cortisol/cortisone ratio, and vascular function was measured using strain-gauge plethysmography. Endothelial function was measured through incremental brachial artery administration of methacholine (0.3–10 μg/min) and vascular smooth muscle function with incremental verapamil (10–300 μg/min). GA increased the 24-h urinary cortisol/cortisone ratio compared with placebo (P=0.008). GA tended to reduce the FBF (forearm blood flow) response to methacholine (P=0.09) and significantly reduced the FBF response to verapamil compared with placebo (P=0.04). MAP (mean arterial pressure) did not differ between the study conditions. 11β-HSD inhibition attenuated vascular smooth muscle vasodilatory function in healthy humans. Disturbances in cortisol activity resulting from 11β-HSD inactivation is therefore a second plausible mechanism for mineralocorticoid-mediated hypertension in humans.

scholarly journals Tubulin-folding cofactor E deficiency is associated with vascular dysfunction and endoplasmatic reticulum stress of vascular smooth muscle cells

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
P Efentakis ◽  
M Molitor ◽  
S Kossmann ◽  
M Bochenek ◽  
J Wild ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Er Stress ◽  
Vascular Function ◽  
Mononuclear Cells ◽  
Vascular Dysfunction ◽  
Conditional Knockout ◽  
Endoplasmatic Reticulum ◽  
A Genome

Abstract Introduction Endothelial function assessed via flow mediated dilatation (FMD) has shown to predict risk in individuals with established cardiovascular diseases, whereas its predictive value is uncertain in the setting primary prevention. Purpose The aim of the current work was to discover and evaluate novel mediators of vascular dysfunction in the general population and in conditional knock-out transgenic animal models. Methods In order to identify novel targets that were negatively correlated with FMD and investigate their contribution in vascular function, a Genome Wide Association Study (GWAS) of 5,000 participants was performed and subsequently immune cell-, endothelial- and vascular smooth muscle cell (VSMCs)-targeted conditional knockout mouse models were generated and characterized. Results GWAS analysis revealed that single nucleotide polymorphisms (SNPs) in the tubulin folding cofactor E (TBCE) gene were negatively correlated with FMD and TBCE expression in the peripheral blood mononuclear cells (PBMCs). Myelomonocytic cell-targeted TBCE deficiency did not lead to any vascular dysfunction in vivo in the LysM+Cre+/−TBCEfl/fl mice. Endothelial-targeted TBCE deficiency led to an NLR family pyrin domain containing 3 (NLRP3)-dependent activation of the inflammasome in the endothelial cells of Tie2-ERT2Cre+/−TBCEfl/fl mice. Importantly, VSMC-targeted TBCE deficiency was associated with endothelial dysfunction, increased aortic wall thickness and endoplasmatic reticulum (ER) stress-mediated VSMC hyperproliferation in vivo (SMMHC-ERT2Cre+/−TBCEfl/fl), paralleled by calnexin upregulation. Administration of the blood pressure hormone angiotensin II exacerbated the vascular dysfunction and phenotype. Administration of the ER stress modulator tauroursodeoxycholic acid to the SMMHC-ERT2Cre+/−TBCEfl/fl mice reversed vascular dysfunction, paralleled by induction of Raptor/Beclin-1-dependent autophagy both in vitro and in vivo. Conclusion TBCE and tubulin homeostasis in the vascular musculature seem to be novel markers of vascular function and represent a new druggable target for the treatment of ER-stress-mediated vascular dysfunction. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): This work was supported by grants of the German Federal Ministry for Education and Research (BMBF01EO1003 and BMBF01EO1503), the DFG Major Research Instrumentation Programme (DFG INST 371/47-1 FUGG) as well as the Boehringer Ingelheim Foundation. PW received funds from the German Research Foundation in support of his work (DFG WE4361-4-1 and WE 4361/7-1). KS, TM and PW are PIs of the DZHK.

Altered Vascular Contractilities Associated with the Applications of Irreversible Electroporation

2020 ◽  
Author(s):  
David A Ramirez ◽  
Weston Upchurch ◽  
Paul A Iaizzo
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Vascular Function ◽  
Irreversible Electroporation ◽  
Collateral Damage ◽  
Cardiac Ablation

Abstract As electroporation therapies become more widely used in the cardiac ablation space, there is a critical need to study the potential effects on surrounding tissues: collateral damage. Here we explored methods to study the effects applying electroporative energies on vascular smooth muscle: i.e., loss of vascular function when exposed to energies needed to induce irreversibly electroporative therapy to the myocardium.

Abstract 310: Deoxycorticosterone Acetate (doca)-salt Exacerbates Hypertension and Vascular Dysfunction in Mice Expressing Dominant Negative Peroxisome Proliferator-activated Receptor-gamma (pparg) in Smooth Muscle

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Pimonrat Ketsawatsomkron ◽  
Deborah R Davis ◽  
Aline M Hilzendeger ◽  
Justin L Grobe ◽  
Curt D Sigmund
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Transgenic Mice ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Critical Role ◽  
Surrogate Marker ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

PPARG, a ligand-activated transcription factor plays a critical role in the regulation of blood pressure and vascular function. We hypothesized that smooth muscle cell (SMC) PPARG protects against hypertension (HT) and resistance vessel dysfunction. Transgenic mice expressing dominant negative PPARG (S-P467L) in SMC or non-transgenic controls (NT) were implanted with DOCA pellet and allowed ad libitum access to 0.15 M NaCl for 21 days in addition to regular chow and water. Blood pressure was monitored by telemetry and mesenteric arterial (MA) function was assessed by pressurized myograph. At baseline, 24-hour mean arterial pressure (MAP) was similar between NT and S-P467L mice, while the transgenic mice were tachycardic. DOCA-salt increased MAP to a much greater degree in S-P467L mice (Δ MAP; S-P467L: +34.2±6.0, NT: +13.3±5.7, p<0.05 vs NT). Heart rate was similarly decreased in both groups after DOCA-salt. Vasoconstriction to KCl, phenylephrine and endothelin-1 did not differ in MA from DOCA-salt treated NT and S-P467L, while the response to vasopressin was significantly reduced in S-P467L after DOCA-salt (% constriction at 10-8 M, S-P467L: 31.6±5.6, NT: 46.7±3.8, p<0.05 vs NT). Urinary copeptin, a surrogate marker for arginine vasopressin was similar in both groups regardless of treatment. Vasorelaxation to acetylcholine was slightly impaired in S-P467L MA compared to NT at baseline whereas this effect was further exaggerated after DOCA-salt (% relaxation at 10-5 M, S-P467L: 56.1±8.3, NT: 79.4±5.6, p<0.05 vs NT). Vascular morphology at luminal pressure of 75 mmHg showed a significant increase in wall thickness (S-P467L: 18.7±0.8, NT: 16.0±0.4, p<0.05 vs NT) and % media/lumen (S-P467L: 8.4±0.3, NT: 7.1±0.2, p<0.05 vs NT) in S-P467L MA after DOCA-salt. Expression of tissue inhibitor of metalloproteinases (TIMP)-4 and regulator of G-protein signaling (RGS)-5 transcript were 2- and 3.5-fold increased, respectively, in MA of NT with DOCA-salt compared to NT baseline. However, this induction was markedly blunted in S-P467L MA. We conclude that interference with PPARG function in SMC leads to altered gene expression crucial for normal vascular homeostasis, thereby sensitizing the mice to the effects of DOCA-salt induced HT and vascular dysfunction.

Abstract P281: Vascular Remodeling And Impaired Vascular Smooth Muscle Cell Plasticity In Age And Sex-dependent Hypertension

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Razie Amraei ◽  
Kayla Nist ◽  
Jesse Moreira ◽  
Richard D Wainford
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Abdominal Aorta ◽  
Vascular Remodeling ◽  
Vascular Dysfunction ◽  
Renal Arteries ◽  
Cell Plasticity ◽  
Sd Rats ◽  
Age And Sex

Aim: Hypertension (HTN) and aging are associated with the development of vascular dysfunction. We speculated that vascular smooth muscle cell plasticity and vascular remodeling play major roles in age and sex-dependent HTN. Methods: Male and female Sprague-Dawley (SD) rats aged 3 and 16-months-old (N=6/group) were housed under standard conditions. Blood pressure was measured via femoral artery cannulation and sympathetic tone to the vasculature was estimated by ganglion blockade via Hexamethonium (30mg/Kg IV). PBS-perfused abdominal aorta and renal arteries were collected and immunoblotting was performed following protein extraction. Results: Male SD rats, but not females, develop HTN and increased sympathetic tone with age. Aged hypertensive male rats, but not aged normotensive females, exhibit reduced p-Erk1/2 and p-eNos levels in both abdominal aorta and renal arteries. α-Smooth Muscle Actin significantly increased in aged male abdominal aorta. Elevated c-Src was observed in aged female abdominal aorta and p-c-Src was reduced in aged male abdominal aorta. Caveolin-1 changed oppositely in young and aged abdominal aorta and renal arteries of two sexes. Conclusions: Our data suggest that artery-specific changes of key signaling molecules contribute to impaired vascular smooth muscle plasticity and vascular dysfunction in aged hypertensive male but not in aged normotensive female rats.

scholarly journals Low-intensity interval exercise training attenuates coronary vascular dysfunction and preserves Ca2+-sensitive K+ current in miniature swine with LV hypertrophy

2011 ◽  
Vol 301 (4) ◽  
pp. H1687-H1694 ◽  
Author(s):  
Craig A. Emter ◽  
Darla L. Tharp ◽  
Jan R. Ivey ◽  
Venkataseshu K. Ganjam ◽  
Douglas K. Bowles
Keyword(s):  
Smooth Muscle ◽  
Exercise Training ◽  
Smooth Muscle Cell ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Miniature Swine ◽  
Vascular Conductance ◽  
Coronary Smooth Muscle ◽  
Interval Exercise ◽  
Low Intensity

Coronary vascular dysfunction has been observed in several models of heart failure (HF). Recent evidence indicates that exercise training is beneficial for patients with HF, but the precise intensity and underlying mechanisms are unknown. Left ventricular (LV) hypertrophy can play a significant role in the development of HF; therefore, the purpose of this study was to assess the effects of low-intensity interval exercise training on coronary vascular function in sedentary (HF) and exercise trained (HF-TR) aortic-banded miniature swine displaying LV hypertrophy. Six months postsurgery, in vivo coronary vascular responses to endothelin-1 (ET-1) and adenosine were measured in the left anterior descending coronary artery. Baseline and maximal coronary vascular conductance were similar between all groups. ET-1-induced reductions in coronary vascular conductance ( P < 0.05) were greater in HF vs. sedentary control and HF-TR groups. Pretreatment with the ET type A (ETA) receptor blocker BQ-123 prevented ET-1 hypersensitivity in HF animals. Whole cell voltage clamp was used to characterize composite K+ currents ( IK+) in coronary smooth muscle cells. Raising internal Ca2+ from 200 to 500 nM increased Ca2+-sensitive K+ current in HF-TR and control, but not HF animals. In conclusion, an ETA-receptor-mediated hypersensitivity to ET-1, elevated resting LV wall tension, and decreased coronary smooth muscle cell Ca2+-sensitive IK+ was found in sedentary animals with LV hypertrophy. Low-intensity interval exercise training preserved normal coronary vascular function and smooth muscle cell Ca2+-sensitive IK+, illustrating a potential mechanism underlying coronary vascular dysfunction in a large-animal model of LV hypertrophy. Our results demonstrate the potential clinical impact of exercise on coronary vascular function in HF patients displaying pathological LV hypertrophy.

Vascular smooth muscle Gq signaling is involved in high blood pressure in both induced renal and genetic vascular smooth muscle-derived models of hypertension

2007 ◽  
Vol 293 (5) ◽  
pp. H3072-H3079 ◽  
Author(s):  
David M. Harris ◽  
Heather I. Cohn ◽  
Stéphanie Pesant ◽  
Rui-Hai Zhou ◽  
Andrea D. Eckhart
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Renal Artery ◽  
Renal Artery Stenosis ◽  
Antihypertensive Therapy ◽  
High Blood Pressure ◽  
Vascular Function ◽  
Artery Stenosis ◽  
Ang Ii

More than 30% of the US population has high blood pressure (BP), and less than a third of people treated for hypertension have it controlled. In addition, the etiology of most high BP is not known. Having a better understanding of the mechanisms underlying hypertension could potentially increase the effectiveness of treatment. Because Gq signaling mediates vasoconstriction and vascular function can cause BP abnormalities, we were interested in determining the role of vascular smooth muscle (VSM) Gq signaling in two divergent models of hypertension: a renovascular model of hypertension through renal artery stenosis and a genetic model of hypertension using mice with VSM-derived high BP. Inhibition of VSM Gq signaling attenuated BP increases induced by renal artery stenosis to a similar extent as losartan, an ANG II receptor blocker and current antihypertensive therapy. Inhibition of Gq signaling also attenuated high BP in our genetic VSM-derived hypertensive model. In contrast, BP remained elevated 25% following treatment with losartan, and prazosin, an α1-adrenergic receptor antagonist, only decreased BP by 35%. Inhibition of Gq signaling attenuated VSM reactivity to ANG II and resulted in a 2.4-fold rightward shift in EC50. We also determined that inhibition of Gq signaling was able to reverse VSM hypertrophy in the genetic VSM-derived hypertensive model. These results suggest that Gq signaling is an important signaling pathway in two divergent models of hypertension and, perhaps, optimization of antihypertensive therapy could occur with the identification of particular Gq-coupled receptors involved.

Hemodynamic and biochemical adaptations to vascular smooth muscle overexpression of p22phox in mice

2005 ◽  
Vol 288 (1) ◽  
pp. H7-H12 ◽  
Author(s):  
Karine Laude ◽  
Hua Cai ◽  
Bruno Fink ◽  
Nyssa Hoch ◽  
David S. Weber ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Protein Expression ◽  
Vascular Function ◽  
Calcium Ionophore ◽  
No Production ◽  
Ros Production ◽  
Enos Expression ◽  
Compensatory Response ◽  
Protein Levels

Protein levels and polymorphisms of p22 phox have been suggested to modulate vascular NAD(P)H oxidase activity and vascular production of reactive oxygen species (ROS). We sought to determine whether increasing p22 phox expression would alter vascular ROS production and hemodynamics by targeting p22 phox expression to smooth muscle in transgenic (Tg) mice. Aortas of Tg p22smc mice had increased p22 phox and Nox1 protein levels and produced more superoxide and H2O2. Surprisingly, endothelium-dependent relaxation and blood pressure in Tg p22smc mice were normal. Aortas of Tg p22smc mice produced twofold more nitric oxide (NO) at baseline and sevenfold more NO in response to calcium ionophore as detected by electron spin resonance. Western blot analysis revealed a twofold increase in endothelial NO synthase (eNOS) protein expression in Tg p22smc mice. Both eNOS expression and NO production were normalized by infusion of the glutathione peroxidase mimetic ebselen or by crossing Tg p22smc mice with mice overexpressing catalase. We have previously found that NO stimulates extracellular superoxide dismutase (ecSOD) expression in vascular smooth muscle. In keeping with this, aortic segments from Tg p22smc mice expressed twofold more ecSOD, and chronic treatment with the NOS inhibitor NG-nitro-l-arginine methyl ester normalized this, suggesting that NO regulates ecSOD protein expression in vivo. These data indicate that chronic oxidative stress caused by excessive H2O2 production evokes a compensatory response involving increased eNOS expression and NO production. NO in turn increases ecSOD protein expression and counterbalances increased ROS production leading to the maintenance of normal vascular function and hemodynamics.

scholarly journals Emblic Leafflower (Phyllanthus emblica L.) Fruits Ameliorate Vascular Smooth Muscle Cell Dysfunction in Hyperglycemia: An Underlying Mechanism Involved in Ellagitannin Metabolite Urolithin A

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Junxuan Zhou ◽  
Cong Zhang ◽  
Guo-Hua Zheng ◽  
Zhenpeng Qiu
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Vascular Function ◽  
Vascular Complications ◽  
Phyllanthus Emblica ◽  
Fruit Consumption ◽  
Urolithin A

Ellagitannins in Phyllanthus emblica L. (emblic leafflower fruits) have been thought of as the beneficial constituents for ameliorating endocrinal and metabolic diseases including diabetes. However, the effect of emblic leafflower fruits on diabetic vascular complications involved in ellagitannin-derived urolithin metabolites is still rare. In this study, acetylcholine-induced endothelium-independent relaxation in aortas was facilitated upon emblic leafflower fruit consumption in the single dose streptozotocin-induced hyperglycemic rats. Emblic leafflower fruit consumption also suppressed the phosphorylation of Akt (Thr308) in the hyperglycemic aortas. More importantly, urolithin A (UroA) and its derived phase II metabolites were identified as the metabolites upon emblic leafflower fruit consumption by HPLC-ESI-Q-TOF-MS. Moreover, UroA reduced the protein expressions of phosphor-Akt (Thr308) and β-catenin in a high glucose-induced A7r5 vascular smooth muscle cell proliferation model. Furthermore, accumulation of β-catenin protein and activation of Wnt signaling in LiCl-triggered A7r5 cells were also ameliorated by UroA treatment. In conclusion, our data demonstrate that emblic leafflower fruit consumption facilitates the vascular function in hyperglycemic rats by regulating Akt/β-catenin signaling, and the effects are potentially mediated by the ellagitannin metabolite urolithin A.

scholarly journals MicroRNA regulation of BMP signaling; cross-talk between endothelium and vascular smooth muscle cells

2018 ◽  
Author(s):  
Charlene Watterston ◽  
Lei Zeng ◽  
Abidemi Onabadejo ◽  
Sarah J Childs
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Vascular Function ◽  
Muscle Cells ◽  
Phenotypic Switching ◽  
Vascular Stability ◽  
Bmp Signalling

AbstractVascular smooth muscle cells (vSMC) are essential to the integrity of blood vessels, and therefore an attractive target of therapeutics aimed at improving vascular function. Smooth muscle cells are one of the few cell types that maintain plasticity and can switch phenotypes from differentiated (contractile) to de-differentiated (synthetic) and vice versa. As small regulatory transcripts, miRNAs act as genetic ‘fine tuners’ of posttranscriptional events and can act as genetic switches promoting phenotypic switching. The microRNAmiR26atargets the BMP signalling effector,smad1. We show that loss ofmiR26leads to hemorrhage (a loss of vascular stability)in vivo, suggesting altered vascular differentiation. Reduction inmiR26alevels increasessmad1mRNA and phospho-Smad1 (pSmad1) levels. We show that increasing BMP signalling by overexpression ofsmad1also leads to hemorrhage and that normalization of Smad1 levels through double knockdown ofmiR26andsmad1rescues hemorrhage suggesting a direct relationship betweenmiR26andsmad1and vascular stability. Using a BMP genetic reporter and pSmad1 staining we show that the effect ofmiR26on vascular instability is non-autonomous; BMP signalling is active in embryonic endothelial cells, but not in smooth muscle cells. Nonetheless, increased BMP signalling due to loss ofmiR26results in an increase inacta2-expressing smooth muscle cell numbers and promotes a differentiated smooth muscle morphology. Taken together our data suggests thatmiR26modulates BMP signalling in endothelial cells and indirectly promotes a differentiated smooth muscle phenotype. Our data also suggests that crosstalk from BMP-responsive endothelium to smooth muscle is important for its differentiation.

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