Endothelium-dependent Vascular Relaxation Research Articles

LCZ696, an Angiotensin Receptor-Neprilysin Inhibitor, Ameliorates Endothelial Dysfunction in Diabetic C57BL/6 Mice.

LCZ696 (sacubitril/valsartan) exerts cardioprotective effects. Recent studies have suggested that it improves the endothelial function; however, the underlying mechanisms have not been thoroughly investigated. We investigated whether LCZ696 ameliorates diabetes-induced endothelial dysfunction. Diabetes was induced using streptozotocin in 8-week-old male C57BL/6 mice. Diabetic mice were randomly assigned to receive LCZ696 (100 mg/kg/day), valsartan (50 mg/kg/day), or a vehicle for three weeks. The endothelium-dependent and endothelium-independent vascular responses of the aortic segments were determined based on the response to acetylcholine and sodium nitroprusside, respectively. Human umbilical vein endothelial cells (HUVEC) and aortic segments obtained from C57BL/6 mice were used to perform in vitro and ex vivo experiments, respectively. LCZ696 and valsartan reduced the blood pressure in diabetic mice (P＜0.05). The administration of LCZ696 (P＜0.001) and valsartan (P＜0.01) ameliorated endothelium-dependent vascular relaxation, but not endothelium-independent vascular relaxation, under diabetic conditions. LCZ696, but not valsartan, increased eNOSSer1177 (P=0.06) and Akt (P＜0.05) phosphorylation in the aorta. In HUVEC, methylglyoxal (MGO), a major precursor of advanced glycation end products, decreased eNOSSer1177 phosphorylation (P＜0.05) and increased eNOSThr495 phosphorylation (P＜0.001). However, atrial natriuretic peptide (ANP) reversed these effects. ANP also ameliorated the MGO-induced impairment of endothelium-dependent vascular relaxation in the aortic segments (P＜0.05), although L-NAME completely blocked this effect (P＜0.001). LCZ696 ameliorated diabetes-induced endothelial dysfunction by increasing the bioavailability of ANP. Our findings suggest that LCZ696 has a vascular protective effect in a diabetic model and highlight that it may be more effective than valsartan.

Effects of Platelet-Activating Factor (PAF) on the Mechanical Activities of Lower Urinary Tract and Genital Smooth Muscles.

Since its first discovery as a bioactive phospholipid inducing potent platelet aggregation, platelet-activating factor (PAF) has been shown to be involved in a wide variety of inflammatory and allergic disease states. Many pharmacological studies in the 1980s and 1990s also showed that PAF induces endothelium-dependent vascular relaxation and contraction of various smooth muscles (SMs), including those in the airway, gastrointestinal organs, and uterus. However, since the late 1990s, there have been few reports on the SM contractions induced by PAF. The lower urinary tract (LUT), particularly the urinary bladder (UB) has attracted recent attention in SM pharmacology research because patients with LUT dysfunctions including overactive bladder are increasing as the population ages. In addition, recent clinical studies have implicated the substantial role of PAF in the inflammatory state in LUT because its production increases with smoking and with cancer. However, the effects of PAF on mechanical activities of LUT SMs including UBSM have not been investigated to date. Recently, we found that PAF very strongly increased mechanical activities of UBSM in guinea pigs and mice, and partly elucidated the possible mechanisms underlying these actions of PAF. In this review, we describe the effects of PAF on LUT SMs by introducing our recent findings obtained in isolated UBSMs and discuss the physiological and pathophysiological significance. We also introduce our data showing the effects of PAF on the SM mechanical activities of genital tissues (prostate and vas deferens).

Curcumin alone not combined with piperine exerts cardioprotective effects in pressure-overload rats by increasing glucagon-like peptide-1 receptor signaling and additional properties

Background and aimCurcumin has shown significant cardiovascular protective effects. However, the low bioavailability limits its practical application. As a natural bioenhancer, piperine is expected to increase the bioavailability of curcumin, and then, enhance its beneficial effects. Meanwhile, glucagon-like peptide-1 receptor (GLP-1R) signaling has been confirmed to be involved in the regulation of cardiovascular events. Herein, this study aimed to investigate whether piperine could enhance the beneficial effects of curcumin in pressure-overload rats and whether GLP-1/GLP-1R signaling is involved in their action mechanism. Methods and resultsMale Sprague-Dawley (SD) adult rats were subjected to abdominal aortic constriction (AAC) surgery to 16 weeks, which elevated blood pressure and induced cardiac hypertrophy. Curcumin (100 mg/kg/day) or/and piperine (20 mg/kg/day) were orally given for 4 weeks from the 17th week after AAC surgery. Curcumin alone treatment significantly lowered blood pressure, ameliorated cardiovascular remodeling, improved left ventricular performance and endothelium-dependent vascular relaxation. Accompanied by these results, GLP-1R expression in the myocardium was up-regulated. Piperine alone also exhibited a certain positive inotropic cardiac activity, but the effect was less significant. The combination of curcumin and piperine didn't show enhanced cardiovascular protective effects relative to curcumin, along with decreased fasting serum GLP-1 level and GLP-1R expression in the myocardium. ConclusionCurcumin exerts cardiovascular protective effects in pressure-overload rats by upregulating GLP-1R, and inhibiting of GLP-1/GLP-1R signaling pathway may be related to the limited beneficial effects of combination of curcumin and piperine. This study provides a new thinking that oral administration of some spices may affect cardiovascular function by modulating the GLP-1/GLP-1R system in a mode of gut-heart axis regulation.

Protective Effects of Thymoquinone on Endothelial Cell Dysfunction in Hypercholesterolemia

Background: Increased reactive oxygen species (ROS) have been implicated as important mechanisms that contribute to endothelial dysfunction (ED). The administration of thymoquinone in animal models significantly inhibits ROS production. Purpose: The protective effects of thymoquinone on endothelial cell dysfunction were studied in cholesterol-fed rabbits. Thirty rabbits were randomly divided into five groups. Methods: The negative control group was fed a standard diet, the positive control group was fed the same diet with 2 % cholesterol, the Thymoquinone group was fed the same diet with 2 % cholesterol and Thymoquinone 100 mg/Kg BW/day, 200 mg/Kg BW/day or 400 mg/Kg BW/day. Results: The cholesterol-rich diet significantly increased Malondialdehyde (MDA) in the aortic blood vessels, as reflected by Thiobarbituric Acid-Reactive Substances (TBARS), inhibited endothelium-dependent vascular relaxations to acetylcholine and decrease cyclic GMP were compared with vessels from normal rabbits (negative control). In cholesterol-fed rabbits, Thymoquinone treatment decreased MDA in plasma production, improved endothelium-dependent relaxations to acetylcholine and increase cyclic GMP production. Conclusion: These results suggest that dietary treatment of rabbits with thymoquinone may prevent superoxide anion (O2-) induced inactivation of endothelium-dependent relaxing factor (EDRF), improve the endothelium-dependent relaxation to acetylcholine in the aortic blood vessels, and increase cyclic GMP content in aortic of cholesterol-fed rabbits.

Human Soluble Prorenin Receptor Expressed in Adipose Tissue Improves Insulin Sensitivity and Endothelial Function in Obese Female Mice

Increased circulating levels of the soluble prorenin receptor (sPRR), a component of the renin angiotensin system (RAS), plays a role in obesity, glucose, and insulin balance. Additionally, studies show that elevated plasma sPRR in diabetic patients is correlated with hyperglycemia in women but not men. Hence, the current study sought to understand the functional role of circulating human sPRR (HsPRR) produced by the adipose tissue (Adi) on adipogenesis and obesity, glucose homeostasis and insulin sensitivity. Adi-HsPRR mice were generated by breeding human sPRR-Myc-tag transgenic mice with mice expressing Adiponectin/Cre. The mouse model was validated by detecting myc-tagged HsPRR in western blot at 28kD. Adi-HsPRR male and female mice were kept on a low-fat (10% kcal from fat; n=4-9/group) or high-fat diet (60% kcal from fat; n=8-13/group) for 20 weeks. Body weight was recorded weekly and body composition (EchoMRI) was assessed monthly. Intraperitoneal glucose tolerance test (ipGTT) was performed at 12 weeks and insulin tolerance test (ITT) at 14 weeks. At 16 weeks, mice were implanted with radio telemeter to measure blood for 5 consecutive days. At the end of the study, tissues and plasma were collected for biochemical analysis and vascular studies. Adipose HsPRR expression did not change circulating sPRR between groups in mice fed a low-fat diet mouse (M: 3.5±0.5 vs 3.9±0.2 ng/ml, F: 2.3±0.2 vs 3.0±0.2 ng/ml) and high fat-fed females (4.3±0.3 vs 5.4±0.5 ng/ml) but increased plasma sPRR in HFD Adi-HsPRR male mice compared to HFD CTL (5.3±0.4 vs 8.7±0.7 ng/ml p<0.05). Yet, Adi-HsPRR expression did not change body weight and composition, glucose, and insulin balance, nor blood pressure and vascular function in male mice regardless the diet. However, Adi-HsPRR improved insulin sensitivity (438±22 vs 360±14 AUC p<0.05) and endothelium-dependent vascular relaxation (11.7±2.6 vs 19.4±2.5 % p<0.05) in Adi-HsPRR female mice fed an HFD. Blood pressure was similar between groups in males and females on both LFD and HFD. Further analysis showed that Adi-HsPRR increased vasodilator agent, Ang 1-7 (5.1±1.6 vs 16.2±3.0 pmol/L p<0.05) in HFD females which was unchanged in HFD males (10.2±2.4 vs 5.2±1.7 pmol/L). Moreover, Adi-HsPRR reduced gene expression of SREBP1C (1.3±0.2 vs 0.7±0.1 2−ΔΔCT p<0.05) and CD36 (1.5±0.3 vs 0.6±0.1 2−ΔΔCT p<0.05), in gonadal white adipose of HFD females but not in males. Additionally, PPAR gamma mRNA was reduced in HFD Adi-HsPRR females (1.1±0.1 vs 0.6±0.1 2−ΔΔCT p<0.05). Our findings suggest that HsPRR in adipose tissue exerts sex-specific protective effects on insulin sensitivity and endothelial function during obesity, despite similar plasma sPRR levels between control and Adi-HsPRR mice. Thus, our model could be a useful tool to investigate potential antidiabetic effect of adipose sPRR in obese women. This work was supported by National Institutes of Health grants (R01-HL-142969 and R01-HL-1647 to ASL); the National Institute of General Medical Sciences (P30 GM127211); and the University of Kentucky, Center for Clinical and Translational Sciences (UL1TR001998). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Chemical Characterization of Phoenix dactylifera L. Seeds and their Beneficial Effects on the Vascular Response in Hypertensive Rats.

Although Phoenix dactylifera dates are traditionally consumed for their health benefits, no research has been done on the vascular response in hypertensive animals. This study evaluated the vascular relaxation of hydroalcoholic extracts from seeds of three varieties of P. dactylifera; Sukkari seed (SS), Ajwa seed (AS), and Mabroom seed (MS) on L-NAME-induced hypertension and spontaneously hypertensive rats (SHR). Results showed that all extracts (10µg/mL) caused relaxations higher than 60% in the aortic rings precontracted with 10- 6 M phenylephrine in normotensive rats, the SS extract was the most potent. Endothelial nitric oxide (NO) pathway is involved as significantly reduced vascular relaxation in denuded-endothelium rat aorta and with an inhibitor (10- 4 M L-Nω-Nitro arginine methyl ester; L-NAME) of endothelial nitric oxide synthase (eNOS). Confocal microscopy confirmed that 10µg/mL SS extract increases NO generation as detected by DAF-FM fluorescence in intact aortic rings. Consistent with these findings, vascular relaxation in intact aortic rings at 10µg/mL SS extract was significantly decreased in L-NAME-induced hypertensive rats (endothelial dysfunction model), but not in SHR. In both hypertensive models, the denuded endothelium blunted the vascular relaxation. In conclusion, the hydroalcoholic extract of the seed of P. dactylifera (Sukkari, Ajwa and Mabroom varieties) presents a potent endothelium-dependent vascular relaxation, via NO, in normotensive rats as well as in two different models of hypertension. This effect could be mediated by the presence of phenolic compounds identified by UHPLC-ESI-MS/MS, such as protocatechuic acid, and caftaric acid.

Gestational Intermittent Hypoxia Impairs AT2R-Mediated Vascular Protection in Female Offspring on a High-Fat, High-Sucrose Diet.

Gestational intermittent hypoxia (GIH), a hallmark of maternal obstructive sleep apnea, sex-differentially causes hypertension and endothelial dysfunction in adult male offspring but not in females. This study investigated whether the GIH-exposed female offspring, a "protected" group against the hypertensive effects of maternal GIH exposure, exhibit increased susceptibility to hypertension and cardiovascular dysfunction when fed a high-fat high-sucrose (HFHS) diet and whether this effect could be reversed by pharmacological intervention activating the angiotensin II type 2 receptor (AT2R). Female offspring of control and GIH-exposed (10.5% O2, 8 h/d, E10-21) dams were assigned either an HFHS diet or a standard diet from 12 weeks of age. Blood pressure was monitored. At 28 weeks, a systemic CGP42112 (AT2R agonist) or saline infusion was administered through the osmotic pump. At 30 weeks, the heart was weighed and collected for H&E staining, mesenteric arteries for vascular reactivity assessment and protein analysis, and plasma for ELISA. The HFHS diet induced similar increases in body weight gain and blood pressure in control and GIH female offspring. HFHS feeding did not affect heart structure, but impaired endothelial-dependent vascular relaxation with associated decreased AT2R and eNOS expression and reduced plasma bradykinin levels in both control and GIH offspring. CGP42112 administration effectively mitigated HFHS-induced hypertension and endothelial dysfunction only in control offspring, accompanied by restored AT2R, eNOS, and bradykinin levels, but not in the GIH counterparts. These findings suggest that GIH induces endothelial dysfunction and AT2R insensitivity in female offspring exposed to an HFHS diet.

Physalis minima leaf extract improves endothelium-dependent vasodilation and decreases blood pressure in ovariectomized rats

This study examined the impact of methanol extract of Physalis minima leaf (MEP) on vascular function and blood pressure in ovariectomized (OVX) rats simulating postmenopausal syndrome. Thirty Wistar rats underwent bilateral ovariectomy. After five weeks, OVX rats were divided into groups, receiving MEP at doses of 500, 1,500, and 2,500 mg/kg BW for four weeks. Two groups served as OVX controls (5-week and 9-week OVX rats). Six sham-operated rats were included as a control. Thoracic aortic rings were isolated for endothelium-dependent vascular relaxation analysis. Endothelial cell count was determined via hematoxylin-eosin staining. Systolic blood pressure (SBP) was measured using a tail-cuff method. Results showed significant (p < 0.01) vascular relaxation decline in 9-week OVX rats. MEP at 1,500 and 2,500 mg/kg BW restored vascular dilation. Endothelial cell number decreased significantly (p < 0.0001) in 5-week and 9-week OVX rats. MEP at 2,500 mg/kg BW raised endothelial cell numbers significantly (p < 0.0001). SBP increased significantly (p < 0.0001) in 9-week OVX rats. MEP at 1,500 mg/kg BW lowered SBP, nearing sham levels, while 2,500 mg/kgBW further reduced SBP significantly (p < 0.0001). Physalis minima extract has the potential to treat postmenopausal vascular issues and hypertension. The strong hypotensive effect at the highest dose emphasizes dosage determination and potential side effects investigation.

Plasmacytoid dendritic cells contribute to vascular endothelial dysfunction in type 2 diabetes.

Type 2 diabetes (T2D) is associated with an increased risk of cardiovascular disease due to macro- and microvascular dysfunction. This study aimed to investigate the potential involvement of plasmacytoid dendritic cells (pDCs) in T2D-related vascular dysfunction. pDCs were isolated from db/db and control mice. It was found that pDCs from db/db mice impaired endothelial cell eNOS phosphorylation in response to ATP and decreased vascular endothelium-dependent relaxation compared to pDCs from control mice. Moreover, isolated CD4+ cells from control mice, when stimulated overnight with high glucose and lipids, and isolated pDCs from db/db mice, display elevated levels of ER stress, inflammation, and apoptosis markers. Flow cytometry revealed that pDC frequency was higher in db/db mice than in controls. In vivo, the reduction of pDCs using anti-PDCA-1 antibodies in male and female db/db mice for 4 weeks significantly improved vascular endothelial function and eNOS phosphorylation. pDCs may contribute to vascular dysfunction in T2D by impairing endothelial cell function. Targeting pDCs with anti-PDCA-1 antibodies may represent a promising therapeutic strategy for improving vascular endothelial function in T2D patients. This study provides new insights into the pathogenesis of T2D-related vascular dysfunction and highlights the potential of immunomodulatory therapies for treating this complication. Further studies are warranted to explore the clinical potential of this approach.

Abstract 12477: ER Stress Chop Depletion in Endothelial Cells Protects From Renovascular Hypertension Pathogenesis

Introduction: Renovascular hypertension poses a significant risk for cardiovascular diseases, with endoplasmic reticulum (ER) stress playing a critical role in their development. However, the specific impact of ER stress-induced C/EBP homologous protein (CHOP) expression in endothelial cells on renovascular hypertension-induced cardiovascular complications remains unexplored. This study investigates the effects of disrupting ER stress CHOP in endothelial cells on microvascular dysfunction associated with renovascular hypertension. Hypothesis: We hypothesize that deleting ER stress CHOP in endothelial cells (EC) can mitigate renovascular hypertension-induced vascular endothelial dysfunction. Methods: Eight-week-old male and female mice (CHOP flx/flx and EC CHOP-/- ) were divided into eight groups: control groups undergoing a sham operation for 4 weeks and renovascular hypertension groups subjected to 2-kidney-1-clip (2K1C) surgery for 4 weeks. Body weight, blood pressure, running performance, cardiac hypertrophy and fibrosis, lung edema, inflammation, vascular endothelial function, and signaling were assessed. Results: Male and female CHOP flx/flx mice subjected to 2K1C for four weeks exhibited hypertension, cardiac hypertrophy and fibrosis, lung edema, impaired running performance, and endothelium-dependent vascular relaxation dysfunction. In contrast, male and female EC CHOP-/- mice subjected to 2K1C for four weeks were protected against the pathogenesis of renovascular hypertension. Furthermore, mesenteric resistance arteries from CHOP flx/flx mice displayed reduced endothelial nitric oxide synthase (eNOS) phosphorylation, while EC HOP-/- mice showed no such effect. Conclusions: These findings emphasize the significance of targeting ER stress CHOP in endothelial cells of male and female mice to protect against the development and pathogenesis of renovascular hypertension.

Varied effects of tobacco smoke and e-cigarette vapor suggest that nicotine does not affect endothelium-dependent relaxation and nitric oxide signaling

Chronic smoking causes dysfunction of vascular endothelial cells, evident as a reduction of flow-mediated dilation in smokers, but the role of nicotine is still controversial. Given the increasing use of e-cigarettes and other nicotine products, it appears essential to clarify this issue. We studied extracts from cigarette smoke (CSE) and vapor from e-cigarettes (EVE) and heated tobacco (HTE) for their effects on vascular relaxation, endothelial nitric oxide signaling, and the activity of soluble guanylyl cyclase. The average nicotine concentrations of CSE, EVE, and HTE were 164, 800, and 85 µM, respectively. At a dilution of 1:3, CSE almost entirely inhibited the relaxation of rat aortas and porcine coronary arteries to acetylcholine and bradykinin, respectively, while undiluted EVE, with a 15-fold higher nicotine concentration, had no significant effect. With about 50% inhibition at 1:2 dilution, the effect of HTE was between CSE and EVE. Neither extract affected endothelium-independent relaxation to an NO donor. At the dilutions tested, CSE was not toxic to cultured endothelial cells but, in contrast to EVE, impaired NO signaling and inhibited NO stimulation of soluble guanylyl cyclase. Our results demonstrate that nicotine does not mediate the impaired endothelium-dependent vascular relaxation caused by smoking.

The Influence of KE and EW Dipeptides in the Composition of the Thymalin Drug on Gene Expression and Protein Synthesis Involved in the Pathogenesis of COVID-19.

Thymalin is an immunomodulatory drug containing a polypeptide extract of thymus that has demonstrated efficacy in the therapy of acute respiratory distress syndrome and chronic obstructive pulmonary disease, as well as in complex therapy related to severe COVID-19 in middle-aged and elderly patients.. KE and EW dipeptides are active substances of Thymalin. There is evidence that KE stimulates cellular immunity and nonspecific resistance in organisms, exerting an activating effect on macrophages, blood lymphocytes, thymocytes, and neutrophils, while EW reduces angiotensin-induced vasoconstriction and preserves endothelium-dependent vascular relaxation by inhibiting ACE2, the target protein of SARS-CoV-2. However, the mechanism of the immunomodulatory action of Thymalin, KE, and EW during COVID-19 remains unclear. To identify the potential mechanism of action underlying the immunomodulatory activity of Thymalin and its active components, EW and KE dipeptides, we assessed inflammatory response in the context of COVID-19. Interactions between EW and KE dipeptides and double-stranded DNA (dsDNA) were investigated by molecular modeling and docking using ICM-Pro. Analysis of the possible effect of EW and KE dipeptides on gene expression and protein synthesis involved in the pathogenesis of COVID-19 was conducted through the use of bioinformatics methods, including a search for promoter sequences in the Eukaryotic Promoter Database, the determination of genes associated with the development of COVID-19 using the PathCards database of human biological pathways (pathway unification database), identification of the relationship between proteins through cluster analysis in the STRING database ('Search Tool for Retrieval of Interacting Genes/Proteins'), and assessment of the functional enrichment of protein-protein interaction (PPI) using the terms of gene ontology (GO) and the Markov cluster algorithm (MCL). After that, in vitro studying of a lipopolysaccharide (LPS)-induced model of inflammation using human peripheral blood mononuclear cells was performed. ELISA was applied to assess the level of cytokines (IL-1β, IL-6, TNFα) in the supernatant of cells with or without the impact of EW and KE peptides. Blood samples were obtained from four donors; for each cytokine, ELISA was performed 2-4 times, with two parallel experimental or control samples for each experiment (experiments to assess the effects of peptides on LPS-stimulated cells were repeated four times, while additional experiments with unstimulated cells were performed two times). Using molecular docking, GGAG was found to be the best dsDNA sequence in the classical B-form for binding the EW dipeptide, while GCGC is the preferred dsDNA sequence in the curved nucleosomal form for the KE dipeptide. Cluster analysis revealed that potential target genes for the EW and KE peptides encode the AKT1 and AKT2 proteins involved in the development of the cytokine storm. The specific targets for the EW peptide are the ACE2 and CYSLTR1 genes, and specific target for the KE peptide is the CHUK gene. Protein products of the ACE2, CYSLTR1, and CHUK genes are functionally associated with IL-1β, IL-6, TNF-α, IL-4, and IL-10 cytokines. An in vitro model of an inflammatory reaction demonstrated that Thymalin and EW and KE dipeptides reduced the synthesis of IL-1β, IL-6, and TNF-α cytokines in human peripheral blood mononuclear cells by 1.4-6.0 times. The immunomodulatory effect of Thymalin under the inflammatory response conditions in COVID-19 is based on the potential ability of its active components, EW and KE dipeptides, to regulate protein synthesis involved in the development of the cytokine storm.

Hyperandrogenism Protects Against High Blood Pressure by Nongenomic Mechanisms and Obesity Causes Hypertension in Females with Polycystic Ovary Syndrome

ABSTRACT Background Androgens induce vasorelaxation and reduce blood pressure in different mammals, including humans. Most women with polycystic ovary syndrome (PCOS), with hyperandrogenism, are obese and exhibit hypertension; thus, the fact that androgens increase blood pressure (BP) is controversial. Our aim was to determine whether hypertension is produced by androgen excess and/or obesity. Methods Experiments were performed in dehydroepiandrosterone; (DHEA, s.c)-induced PCOS model. BP from nonobese and obese rats with PCOS (fed a normal or high-fat diet, respectively) was evaluated weekly for 10 weeks by plethysmography and compared between them. We determined whether androgen receptors are responsible for androgen action on BP in rats with PCOS; a group of DHEA-treated rats was implanted with pellets of an antiandrogen and was compared with nonobese rats with PCOS. Isometric tension from aortas of nonobese and obese rats was recorded and compared to explore the integrity of the vascular endothelium when acetylcholine-induced endothelium-dependent vascular relaxation on phenylephrine contraction. Additionally, BP was obtained from 30 women diagnosed with PCOS: nonobese (BMI ≤25) and obese women (BMI ≥35) and compared with healthy counterparts; 15 obese and 15 nonobese women. Results Nonobese rats and women with PCOS showed hypotension, while obese rats and women with PCOS displayed hypertension. Healthy obese women were hypertensive and nonobese women remained normotensive. Antiandrogen did not modify the BP values in nonobese rats with PCOS, and obese rats with PCOS revealed marked endothelial dysfunction. Conclusions Our findings show that obesity is responsible for hypertension in PCOS and partial endothelial damage was observed, which may contribute to elevated BP. Remarkably, hyperandrogenism is capable of regulating BP to low values that are androgen receptor-independent.

Recovery of Endothelium-dependent vascular relaxation impairment in convalescent COVID-19 patients: Insight from a pilot study

BackgroundEndothelial dysfunction is a key-feature in acute COVID-19. However, follow-up data regarding endothelial dysfunction and injury after COVID-19 infection are lacking. We aimed to investigate the changes in endothelium-dependent vasorelaxation at baseline and four months after hospital discharge in COVID-19 patients. MethodsTwenty COVID-19 patients were compared to 24 healthy controls. Clinical and morphological data were collected after hospital admission for SARS-CoV-2 infection and reactive hyperaemia index (RHI) measurement was performed with a delay between 24 and 48 h after hospital admission and four months after hospital discharge in the outpatient clinics. Blood tests including inflammatory markers and measurement of post-occlusive vasorelaxation by digital peripheral arterial tonometry were performed at both visits. ResultsAt baseline, COVID-19 patients exhibited reduced RHI compared to controls (p < 0.001), in line with an endothelial dysfunction. At four months follow-up, there was a 51% increase in the RHI (1.69 ± 0.32 to 2.51 ± 0.91; p < 0.01) in favor of endothelium-dependent vascular relaxation recovery. RHI changes were positively correlated with baseline C-reactive protein (r = 0.68; p = 0.02). Compared to COVID-19 patients with a decrease in RHI, COVID-19 patients with an increase in RHI beyond the day-to-day variability (i.e. >11%) had less severe systemic inflammation at baseline. ConclusionConvalescent COVID-19 patients showed a recovery of systemic artery endothelial dysfunction, in particular patients with lower inflammation at baseline. Further studies are needed to decipher the interplay between inflammation and endothelial dysfunction in COVID-19 patients.

Aberrant hyper-expression of the RNA binding protein GIGYF2 in endothelial cells modulates vascular aging and function

Vascular endothelial cells (ECs) senescence plays a crucial role in vascular aging that promotes the initiation and progression of cardiovascular disease. The mutation of Grb10-interacting GYF protein 2 (GIGYF2) is strongly associated with the pathogenesis of aging-related diseases, whereas its role in regulating ECs senescence and dysfunction still remains elusive. In this study, we found aberrant hyperexpression of GIGYF2 in senescent human ECs and aortas of old mice. Silencing GIGYF2 in senescent ECs suppressed eNOS-uncoupling, senescence, and endothelial dysfunction. Conversely, in nonsenescent cells, overexpressing GIGYF2 promoted eNOS-uncoupling, cellular senescence, endothelial dysfunction, and activation of the mTORC1-SK61 pathway, which were ablated by rapamycin or antioxidant N-Acetyl-l-cysteine (NAC). Transcriptome analysis revealed that staufen double-stranded RNA binding protein 1 (STAU1) is remarkably downregulated in the GIGYF2-depleted ECs. STAU1 depletion significantly attenuated GIGYF2-induced cellular senescence, dysfunction, and inflammation in young ECs. Furthermore, we disclosed that GIGYF2 acting as an RNA binding protein (RBP) enhances STAU1 mRNA stability, and that the intron region of the late endosomal/lysosomal adaptor MAPK and mTOR activator 4 (LAMTOR4) could bind to STAU1 protein to upregulate LAMTOR4 expression. Immunofluorescence staining showed that GIGYF2 overexpression promoted the translocation of mTORC1 to lysosome. In the mice model, GIGYF2flox/flox Cdh-Cre+ mice protected aged mice from aging-associated vascular endothelium-dependent relaxation and arterial stiffness. Our work discloses that GIGYF2 serving as an RBP enhances the mRNA stability of STAU1 that upregulates LAMTOR4 expression through binding with its intron region, which activates the mTORC1-S6K1 signaling via recruitment of mTORC1 to the lysosomal membrane, ultimately leading to ECs senescence, dysfunction, and vascular aging. Disrupting the GIGYF2-STAU1-mTORC1 signaling cascade may represent a promising therapeutic approach against vascular aging and aging-related cardiovascular diseases.

A Selective Mineralocorticoid Receptor Blocker, Esaxerenone, Attenuates Vascular Dysfunction in Diabetic C57BL/6 Mice.

Pharmacological blockade of mineralocorticoid receptors (MRs) is a potential therapeutic approach to reduce cardiovascular complications since MRs play a crucial role in cardiovascular regulation. Recent studies suggest that MR antagonists affect several extrarenal tissues, including vessel function. We investigated the effect of a novel nonsteroidal selective MR blocker, esaxerenone, on diabetes-induced vascular dysfunction. Diabetes was induced by a single dose of streptozotocin in 8-week-old male C57BL/6 mice. Esaxerenone (3 mg/kg/day) or a vehicle was administered by gavage to diabetic mice for 3 weeks. Metabolic parameters, plasma aldosterone levels, and parameters related to renal function were measured. Endothelium-dependent or -independent vascular responses of the aortic segments were analyzed with acetylcholine or sodium nitroprusside, respectively. Human umbilical vein endothelial cells (HUVECs) were used for the in vitro study. Induction of diabetes elevated plasma aldosterone level (P＜0.05) and impaired endothelium-dependent vascular relaxation (P＜0.05). The administration of esaxerenone ameliorated the endothelial dysfunction (P＜0.01) without the alteration of metabolic parameters, blood pressure, and renal function. Esaxerenone improved the eNOSSer1177 phosphorylation in the aorta obtained from diabetic mice (P＜0.05) compared with that in the vehicle-treated group. Furthermore, a major MR agonist, aldosterone, decreased eNOSSer1177 phosphorylation and increased eNOSThr495 phosphorylation in HUVECs, which recovered with esaxerenone. Esaxerenone ameliorated the endothelium-dependent vascular relaxation caused by aldosterone in the aortic segments obtained from C57BL/6 mice (P＜0.001). Esaxerenone attenuates the development of diabetes-induced endothelial dysfunction in mice. These results suggest that esaxerenone has potential vascular protective effects in individuals with diabetes.

Impact of metabolic therapy on the state of cerebral hemodynamics in hypoestrogenemia

Objective. To investigate the impact of therapy with Mildronate® on the state of cerebral hemodynamics, on vascular wall remodeling and endothelial dysfunction in women with hypertension and estradiol deficiency. Subjects and methods. The investigation enrolled 37 patients (mean age, 43.0±3.5 years) with Stage I–II hypertension, reduced estradiol and elevated follicle-stimulating hormone (FSH) levels, who formed a study group. The patients in this group received Mildronate® in addition to standard therapy. A control group consisted of 38 healthy women (mean age 43.5±3.4 years) without chronic diseases affecting intracardiac and cerebral hemodynamics. Complete medical histories were taken from all the patients who underwent a mandatory laboratory test (including estradiol and FSH levels), ECG, and duplex scanning of the great cerebral arteries. Results. The features of vascular bed remodeling, the state of cerebral hemodynamics, and endothelial dysfunction in the examinees can assume that hypoestrogenemia may be a factor contributing to the progression of hypertension and the development of complications, such as cerebrovascular accidents. Conclusion. The study results have shown that Mildronate® is well tolerated by patients and is an effective treatment, showing a positive therapeutic effect on endothelium-dependent vascular relaxation, vascular remodeling, and whole-brain hemodynamics.

Vascular Relaxation and Blood Pressure Lowering Effects of Prunus mume in Rats.

Prunus mume Siebold et Zuccarini is mainly consumed as processed fruits in beverages, vinegar, alcohol, or fruit syrup; studies have reported various functional effects. Many pharmacological and functional studies exist on fruit extracts or processed foods using fruits, however, efficacy studies on various parts of P. mume, including the bark, branches, flowers, and leaves, have not been sufficiently conducted. A previous study revealed that a 70% ethanol extract of P. mume branches induced vascular endothelium-dependent vasorelaxant effects in rat thoracic aortic rings. Therefore, we hypothesized that various parts (the fruits, flowers, leaves, and bark) might have vasorelaxant effects. We evaluated the effects of P. mume extracts on the vascular relaxation of isolated rat thoracic aorta and hypotensive effects in spontaneous hypertensive rats (SHR). A 70% ethanol extract of P. mume bark (PBaE) was the most effective, thus, we investigated its vasorelaxant mechanisms and hypotensive effects. PBaE lowered the blood pressure in SHR and induced the vascular endothelium-dependent relaxation of isolated rat aortic rings via the NO/sGC/cGMP and the PGI2 pathways in the vascular smooth muscle. Potassium channels, such as KCa, KATP, KV, and Kir, were partially associated with a PBaE-induced vasorelaxation. Therefore, PBaE might help prevent and treat hypertension.

Microcirculation and Physical Exercise In Hypertension.

Hypertension is associated with important alterations in the morphology of small arteries and arterioles. Vascular-specific manifestations are changes in the structure and function of vascular smooth muscle cells, extracellular matrix, perivascular tissues, and endothelial cells. Arteriole and capillary remodeling and capillary rarefaction have been observed in hypertensive animals and human beings which contribute to increased vascular resistance. An impairment of different angiogenetic factors, such as VEGF (vascular endothelial growth factor), VEGFR-2 (vascular endothelial growth factor receptor-2), TIMP-1 (tissue inhibitor matrix metalloproteinases-1), and TSP-1 (thrombospondin-1), seems to be responsible for the reduction of the microvascular network. Exercise training has been shown to improve vascular structure and function in hypertension not only in the large arteries but also in the peripheral circulation. Exercise training may regress microvascular remodeling and normalize capillary density, leading to capillary growth possibly by increasing proangiogenic stimuli such as VEGF. Exercise enhances endothelium-dependent vascular relaxation through nitric oxide release increase and oxidative stress reduction. Other mechanisms include improved balance between prostacyclin and thromboxane levels, lower circulating levels of endothelin-1, attenuation of infiltration of immune cells into perivascular adipose tissue, and increase of local adiponectin secretion. In addition, exercise training favorably modulates the expression of several microRNAs leading to a positive modification in muscle fiber composition. Identifying the bioactive molecules and biological mechanisms that mediate exercise benefits through pathways that differ from those used by antihypertensive drugs may help to improve our knowledge of hypertension pathophysiology and facilitate the development of new therapeutic strategies.

7-Hydroxycoumarin Induces Vasorelaxation in Animals with Essential Hypertension: Focus on Potassium Channels and Intracellular Ca2+ Mobilization.

Cardiovascular diseases (CVD) are the deadliest noncommunicable disease worldwide. Hypertension is the most prevalent risk factor for the development of CVD. Although there is a wide range of antihypertensive drugs, there still remains a lack of blood pressure control options for hypertensive patients. Additionally, natural products remain crucial to the design of new drugs. The natural product 7-hydroxycoumarin (7-HC) exhibits pharmacological properties linked to antihypertensive mechanisms of action. This study aimed to evaluate the vascular effects of 7-HC in an experimental model of essential hypertension. The isometric tension measurements assessed the relaxant effect induced by 7-HC (0.001 μM-300 μM) in superior mesenteric arteries isolated from hypertensive rats (SHR, 200-300 g). Our results suggest that the relaxant effect induced by 7-HC rely on K+-channels (KATP, BKCa, and, to a lesser extent, Kv) activation and also on Ca2+ influx from sarcolemma and sarcoplasmic reticulum mobilization (inositol 1,4,5-triphosphate (IP3) and ryanodine receptors). Moreover, 7-HC diminishes the mesenteric artery's responsiveness to α1-adrenergic agonist challenge and improves the actions of the muscarinic agonist and NO donor. The present work demonstrated that the relaxant mechanism of 7-HC in SHR involves endothelium-independent vasorelaxant factors. Additionally, 7-HC reduced vasoconstriction of the sympathetic agonist while improving vascular endothelium-dependent and independent relaxation.