Changes In Endothelial Function Research Articles

Cardiovascular Reactivity to Mental Stress and Adverse Cardiovascular Outcomes in Patients With Coronary Artery Disease.

Acute psychological stress may induce physiological changes predisposing individuals to adverse health outcomes through hemodynamic and vascular effects. We studied the association between the aggregated stress-induced changes in hemodynamic and vascular function tests with adverse cardiovascular outcomes in patients with coronary artery disease, after adjusting for sociodemographic and clinical factors. Individuals with stable coronary artery disease from 2 prospective cohort studies were studied. Hemodynamic reactivity, changes in endothelial function, and vasoconstriction during mental stress were evaluated using changes in rate-pressure product, brachial artery flow-mediated vasodilation, and peripheral arterial tonometry, respectively. A cardiovascular reactivity risk score was calculated by allotting 0 to 3 points for each quartile of increasing abnormality for each of the 3 reactivity responses and summing the quartile points from the MIPS (Mental Stress Ischemia Prognosis Study) to yield a cardiovascular reactivity risk score ranging from 0 to 9. The outcome was a composite of cardiovascular death, nonfatal myocardial infarction, and heart failure hospitalizations during follow-up. A total of 629 participants were included. After adjustment for demographic and traditional risk factors, a blunted hemodynamic response, a greater decrease in flow-mediated vasodilation, and a greater degree of peripheral vasoconstriction to mental stress were all independently associated with a higher risk of adverse outcomes in both cohorts. By adding the cardiovascular reactivity risk score, the C-statistic increased significantly by 10% (P<0.001). Among individuals with stable coronary artery disease, a risk score derived from cardiovascular reactivity to mental stress was predictive of adverse cardiovascular outcomes beyond traditional cardiovascular risk factors.

LncRNA H19 Promotes Angiogenesis in Mouse Pulmonary Artery Endothelial Cells by Regulating the HIF-1α/VEGF Signaling Pathway.

Persistent pulmonary hypertension of the newborn (PPHN) is a syndrome of acute respiratory failure characterized by systemic hypoxemia and elevated pulmonary arterial pressure, which leads to pathological changes in pulmonary vascular remodeling and endothelial cell function. Long non-coding RNA (lncRNA) H19 has been shown to be involved in the regulation of arterial endothelial cell function, but its regulatory role in PPHN is not fully understood. In the present study, mouse pulmonary artery endothelial cells (MPAECs) were cultured in a hypoxic conditions. Subsequently, the regulatory function of lncRNA H19 on MPAECs was explored by constructing adenoviruses knocking down and overexpressing lncRNA H19. The results revealed that the hypoxic conditions could induce the proliferation and migration of MPAECs, as well as the high expression of lncRNA H19 in MPAECs. Knockdown of lncRNA H19 expression in MPAECs reversed hypoxic environment-induced functional changes in endothelial cells, whereas overexpression of lncRNA H19 further enhanced the proliferation and migration of MPAECs. In addition, lncRNA H19 upregulated the hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway through sponge of miNA-20a-5p, which in turn promoted changes in endothelial cell function. LncRNA H19 may interfere with vascular remodeling in hypoxia-induced pulmonary hypertension by upregulating the expression of HIF-1α and VEGF in vascular endothelial cells.

Menstrual cycle and the protective effects of remote ischemic preconditioning against endothelial ischemia/reperfusion injury: comparison with postmenopausal women.

The aim of this study was to determine whether the capacity of remote ischemic preconditioning (IPC) against endothelial ischemia/reperfusion (I/R) injury changes across the menstrual cycle in premenopausal women and to compare IPC responses to postmenopausal women. Thirty-five women were studied (22 premenopausal/13 postmenopausal). Changes in endothelial function were determined during the early follicular vs. the late follicular phase (after positive urine ovulation test; Study 1), vs. the mid-luteal phase (after positive urine progesterone test; Study 2), and vs. estrogen-deficient postmenopausal women; Study 3). Endothelium-dependent vasodilation was assessed by the forearm blood flow (FBF) to reactive hyperemia with/without I/R injury with remote IPC (3 × 5 min cycles of upper arm ischemia). In the premenopausal women, peak FBF responses during the early follicular phase were blunted 20% (P < 0.0001) with I/R injury (from baseline: 23.4 ± 6.2 to 19.5 ± 4.9 mL/100 mL tissue/min) compared with the late follicular/mid-luteal phases despite IPC. In postmenopausal women, peak FBF was diminished (from: 21.1 ± 5.1 to 17.2 ± 4.4 mL/100 mL tissue/min), and total FBF (area under the curve) was decreased a third (-32%; P < 0.001) with I/R injury. Protection from I/R injury was preserved during the late follicular (from baseline: 21.7 ± 5.3 to 24.8 ± 5.9 mL/100 mL tissue/min; P = 0.109) and mid-luteal phases (from: 25.1 ± 3.9 to 27.2 ± 5.7 mL/100 mL tissue/min; P = 0.267). Reduced estrogen during the early follicular phase and the rise in estrogen associated with ovulation and the mid-luteal phase may contribute to changes in IPC-mediated protection in premenopausal women and shed light on how cardioprotection may change with ovarian hormone deficiency with the menopause transition.NEW & NOTEWORTHY The capacity of remote ischemic preconditioning to protect against vascular endothelial ischemia/reperfusion injury varies widely across the phases of the menstrual cycle in healthy premenopausal women. Robust protection was afforded during the late follicular and mid-luteal phases. In contrast, weakened protection was demonstrated during the early follicular phase, with a level of impairment similar to estrogen-deficient postmenopausal women.

Dynamics of endothelial function in patients with arterial hypertension with different cardiovascular risk against the background of antihypertensive therapy

The aim of the work was to investigate the dynamics of endothelial markers in patients with arterial hypertension with different cardiovascular risk under the influence of the prescribed treatment during a year of observation. The first group (with a moderate risk of cardiovascular events) included 48 patients with arterial hypertension (AH). The second group consisted of 54 patients with hypertension and a high risk of cardiovascular events, namely type 2 diabetes. Each group of patients was randomized into two subgroups by blood pressure (BP) medication. In patients of subgroup 1a (n=29) and subgroup 2a (n=35) – the main subgroups – the therapy necessarily included the angiotensin II receptor antagonist losartan potas­sium in a dosage of 50-150 mg/day, depending on the blood pressure level. Patients of subgroup 1b (n=19) and subgroup 2b (n=19) – comparison subgroups were treated with antihypertensive drugs of other first-line groups according to the data of the unified clinical protocol for the treatment of hypertension. According to the ROC analysis, it was determined that the dynamics of endothelin-1 (ET-1) indicators after 9 and 12 months of therapy (a decrease of 12% or more from the initial level) can predict the normalization of indicators of the coagulation and anticoagulation systems with indicators of sensitivity and specificity – 85% (95% CI 62.1-96.6%) and 92.9% (95% CI 76.5-98.9%), respectively. A decrease in the level of Willebrand factor (fV) by 23% or more due to such a treatment time can be used as a prognostic sign in determining the regression of endothelial dysfunction with sensitivity – 75% (95% CI 50.9-91.2%), specificity – 100% (95% CI 87.5-100%). According to the given data, both in the group with moderate and with high cardiovascular risk, there is a relationship between endothelial dysfunction (ED) and the duration of hypertension, indicators of the lipid spectrum and abdominal obesity – factors that increase the viscous resistance of the blood circulation, as well as platelet hyperactivity in the bloodstream. We have also established that according to the dynamics of ET-1 indicators after 9 and 12 months of therapy (decrease by 27% or more from the initial level), it is possible to predict the normalization of indicators of the coagulation and anticoagulation systems with indicators of sensitivity – 81.8% (95% CI 59.7-94.7%), specificity – 90.6% (95% CI 75-97.9%). A decrease in the level of fV by 24.5% or more after a year of treatment can be used as a prognostic sign in determining the regression of endothelial dysfunction with sensitivity – 68.2% (95% CI 45.1-86.1%), specificity – 71.9% (95% CI 53.3-86.2%). The obtained results testify to the dominant role of type 2 diabetes as a factor in platelet disorders of hemostasis. Taking into account the positive dynamics of the above-mentioned markers of ED during the year of treatment, their relationship with the reduction of blood pressure, indicators of the lipid spectrum and abdominal obesity, it should be noted the positive effect of angiotensin II receptor blockers (BRA II) as endothelioprotective drugs. Considering the irrefutable literary data about the absence of thrombomodulin in the blood stream, even its insignificant appearance indicates the presence of endothelial dysfunction. Determining the state and dynamics of changes in endothelial function under the influence of prescribed therapy will make it possible to improve the diagnosis of endothelial function disorders and increase the effectiveness of treatment of patients with hypertension and various cardiovascular risks.

Acute endothelial, blood pressure, and glycemic responses after aerobic sessions in type-2 diabetic with hypertension: A double-blinded randomized study

ObjectivesTo compare the acute response of moderate intensity continuous exercise (MICE) vs moderate intensity interval exercise (MIIE) on endothelial function, post-exercise hypotension (PEH), and glycemia in type 2 diabetes (T2DM) with hypertension. MethodsTwelve T2DM (aged 52.8 ± 3.8 years old) patients with hypertension underwent a randomized cross-over study following isocaloric (200 kcal) protocols: (i) MICE: walk-jogging at 50% of VO2peak, (ii) MIIE session: walking – jogging (stimulus/recovery – 3:3 min each) at 60% of VO2peak followed by recovery at 40% of VO2peak, and (iii) control (CON): lying quietly in a supine position for 30 min. A generalized estimating equation was utilized to verify possible differences over time × session. ResultsThe %FMD (Baseline: 3.59 ± 1.58 vs. 30 min: 6.73 ± 4.34) and the absolute FMD changed after MIIE (Baseline: 0.16 ± 0.10 vs. 30 min: 0.17 ± 0.14). Only absolute FMD changed after MIIE (Baseline: 0.14 ± 0.07 vs. 30 min: 0.16 ± 0.07). Besides, MIIE at 30 min provides higher absolute FMD values when compared to baseline from MICE and baseline, 30 min, and 60 min from control. Regarding blood pressure, no PEH statistical main effect was found. Finally, the glycemia changed at baseline vs. 30 min and 60 min after MIIE (210.5 ± 9.4 vs. 127.6 ± 10.0 and 120 ± 8.9), MICE (219.5 ± 12.7 vs. 125.2 ± 12.0 and 118.2 ± 11.6), and control sessions (215.9 ± 11.8 vs. 187.4 ± 11.2 and 172.6 ± 11.3 mg/dL, p < 0.05). However, MIIE and MICE showed higher decreases compared to the control. ConclusionsMIIE and MICE sessions are similar and effective exercise strategies to induce changes in endothelial function and glycemic responses in type-2 diabetics with hypertension.

Comparative effects of sacubitril/valsartan and ACEI/ARB on endothelial function and arterial stiffness in patients with heart failure: a protocol for systematic review and meta-analysis

IntroductionHeart failure (HF) is a complex syndrome that affects millions of people worldwide and leads to significant morbidity and mortality. Sacubitril/valsartan, a combination drug consisting of a neprilysin inhibitor and...

Vascular endothelial function and its response to moderate-intensity aerobic exercise in trained and untrained healthy young men

30 min of moderate-intensity aerobic exercise per day is recommended, but the response and adaptation of endothelial function (EF) to this exercise remains controversial. The purpose of this study was to determine the changes in EF in endurance trained and untrained individuals before and after this exercise and to compare the differences between trained and untrained individuals. Twelve endurance-trained male college athletes (trained group) and 12 untrained male college students (untrained group) performed a 30-min run at an intensity of 60% VO2max. Brachial artery flow-mediated dilation (FMD) was measured before exercise, 30 min and 60 min after exercise, and the following morning. Resting diameter and maximum diameter showed large time effects (p < 0.001, η2 = 0.533; p < 0.001, η2 = 0.502). Resting diameters at 30 and 60 min after exercise were higher than before exercise in both the untrained and trained groups (p < 0.05), and maximum diameters at 30 min after exercise were higher than before exercise in both the untrained and trained groups (p < 0.01). Resting diameter and maximum diameter also exhibited some group effects (p = 0.055, η2 = 0.157; p = 0.041, η2 = 0.176). Resting diameters and maximum diameters were higher in the trained group than in the untrained group before exercise (p < 0.05). FMD (%) showed no time, group, or time-group interaction effects. 30 min of moderate-intensity aerobic exercise can increase resting and maximal arterial diameters in both trained and untrained young men, but has no effect on FMD. Long-term endurance training has the potential to increase resting and maximal arterial diameters in young men, but not necessarily FMD.

DIFFERENCES IN PROTEASE ACTIVATED RECEPTOR-1 AND THROMBINE LEVELS IN PREECLAMPSIA AND NORMAL PREGNANCY

Introduction: Preeclampsia is a condition caused by alterations in endothelial function during pregnancy. Changes in endothelial function result in an increase in coagulation and microvascular fibrin accumulation, which results in impaired placental perfusion. Thrombin, which converts fibrin to fibrinogen, as well as platelet activity, the fibrinolytic system, and anticoagulants, are all procoagulant circumstances in preeclampsia. Thrombin contributes to the pathogenesis of preeclampsia by increasing the expression of sFlt-1 thereby providing an antiangiogenic response. Protease Activated Receptor-1 (PAR-1) is a mediator of thrombin for coagulation and inflammation in preeclampsia. Inhibition of Protease Activated Receptor-1 expression in trophoblasts can enhance placental angiogenesis and vascular remodeling. Recently, only few studies have assessed the levels of Protease Activated Receptor -7 and thrombin in preeclampsia.Objective: To determine the difference in levels of Protease Activated Receptor-1 and thrombin in preeclampsia and normal pregnancyMethods: This study is observational with a cross-sectional comparative study design. Sampling was conducted from March 2020 to March 2021. A total of 66 patients were investigated, with 33 samples of preeclampsia and 33 samples of normal pregnancy. The independent sample T-test was used for statistical analysis.Results: The mean levels of Protease Activated Receptor-1 in the preeclampsia group were higher at 28.56 ± 7.68 ng/mL while normal pregnancy was 21.67 ± 6.92 ng/mL. The results of statistical tests showed that there was a significant difference in levels of Protease Activated Receptor-1 between the preeclampsia and normal pregnancy groups (p&lt;0.05). The mean thrombin level in the preeclampsia group was higher at 72.23 ± 7.99 ng/mL, while in normal pregnancy it was 63.70 ± 8.92 ng/mL. The difference in thrombin levels between the preeclampsia and normal pregnancy groups was statistically significant (p&lt;0.05).Conclusion: Preeclampsia was associated with greater levels of Protease Activated Receptor-1 and thrombin than normal pregnancy. There was a significant difference in the mean levels of Protease Activated Receptor-1 and thrombin between preeclampsia and normal pregnancy.Keywords: Thrombin, Protease Activated Receptor-1(PAR-1), Preeclampsia

Power-Doppler Ultrasonic Imaging of Peripheral Perfusion in Diabetic Mice.

We explored the capabilities of power-Doppler ultrasonic (PD-US) imaging without contrast enhancement for monitoring changes in muscle perfusion over time. Ischemic recovery was observed in healthy and type II diabetic male and female mice with and without exercise. In separate studies, perfusion was measured during and after 5-min ischemic periods and during four-week recovery periods following irreversible femoral ligation. A goal was to assess how well PD-US estimates tracked the diabetic-related changes in endothelial function that influenced perfusion. The average perfusion recovery time following femoral ligation increased 47% in diabetic males and 74% in diabetic females compared with non-diabetic mice. Flow-mediated dilation in conduit arteries and the reactive hyperemia index in resistive vessels each declined by one half in sedentary diabetic mice compared with sedentary non-diabetic mice. We found that exercise reduced the loss of endothelial function from diabetes in both sexes. The reproducibility of perfusion measurements was limited primarily by our ability to select the same region in muscle and to effectively filter tissue clutter. PD-US measurements can precisely follow site-specific changes in skeletal muscle perfusion related to diabetes over time, which fills the need for techniques capable of regularly monitoring atherosclerotic changes leading to ischemic vascular pathologies.

Carvacrol prevents D-( +)-galactose-induced aging-associated erectile dysfunction by improving endothelial dysfunction and oxidative stress in rats.

Aging is one of the risk factors involved in the development of erectile dysfunction (ED). Growing evidence suggests that oxidative stress is the critical mediator of changes in endothelial function and penile vascular tone in the aging process. Thus, reducing reactive oxygen species (ROS) levels may preserve the bioactivity of the penile vasculature. Antioxidant compounds, such as carvacrol, limit the damage caused by ROS and, therefore, benefit the treatment of ED. Thus, this study aims to evaluate the effects of carvacrol on ED using the D-( +)-galactose aging model. The animals were divided into five groups: control, D-( +)-galactose 150mg/kg, carvacrol 50mg/kg or 100mg/kg, and sildenafil 1.5mg/kg treated daily for 8weeks. The physiological, functional, and morphological characteristics of aging-associated ED were evaluated after treatment with carvacrol. Carvacrol prevented ED in a D-( +)-galactose-induced aging model by reducing hypercontractility, enhancing endothelial dysfunction in the rat corpus cavernosum, and improving endothelial health of rat cavernous endothelial cells. In addition, carvacrol prevented the destruction of erectile components essential for penile erection and promoted a reduction of penile tissue senescence, probably through mechanisms that involve the harmful modulation of oxidative stress. Carvacrol significantly improved the erectile function of rats in a D-( +)-galactose-induced aging model and has excellent potential as a new therapeutic alternative in treating erectile dysfunction.

Hypothyroidism and metabolic cardiovascular disease.

Cardiovascular disease (CVD) remains the leading cause of death worldwide, representing a major health issue of social and economic relevance. Both hyperthyroidism and hypothyroidism are very common in the adult population, and both disorders may contribute to the onset and progression of CVD. After a brief description of the role of thyroid hormones (THs) on the physiology of the cardiovascular system and the potential mechanism that links THs alterations with changes in cardiac function, blood pressure, endothelial function, and lipid levels, we review updated data about the clinical impact of overt hypothyroidism (OH) and subclinical hypothyroidism (SCH) on CV risk, CVD, and mortality. Furthermore, we summarize the current evidence for treating SCH with levothyroxine (L-T4). Several guidelines of distinguished endocrine societies recommend treatment for SCH with TSH higher than 10 mIU/L, where the benefit of L-T4 therapy is more evident for younger people, but still controversial in those aged over 65 years. Based on current knowledge, more research efforts are needed to better address the clinical management of CV risk and CVD in the elderly affected by SCH.

#1073 Changes in endothelial function in patients with impaired central and renal hemodynamics respiratory pathology

Abstract Background and Aims To determine the degree of influence of endothelial dysfunction on the hemodynamics of renal and central vessels in respiratory pathology, as well as to determine the effectiveness of complex therapy regimens with carvedilol. Method Studies were conducted in 26 patients with chronic obstructive pulmonary disease (COPD) of II- III severity (group 1, in whom the level of glomerular filtration rate of the kidneys eGFR CKD-EPI ≥6 ml/min/1.73 m2 was determined) and 32 patients with COPD of IV severity (group 2, they were determined e GFR CKD-EPI ≥60 ml/min/1.73 m2). Patients received one course of ten-day standard therapy (GOLD, 2020) in combination with a beta–blocker drug, T. carvedilol 5 mg (Vertex). Doppler echocardiographic examination of peripheral vessels, heart and renal vessels of patients was performed. Stable metabolites of nitric oxide (Cm NO) in blood plasma, ventilation and perfusion state of the lungs were determined. Results A significant decrease in the functional state of the respiratory system was parallel with a decrease in Cm NO synthesis, which was clearly reflected in the second group (by 11%) compared with the first group (by 7%). Pronounced structural changes with remodeling of the right parts of the heart, as well as a pronounced degree of pancreatic hypertrophy in the second group were accompanied by a sharp change in renal filtration function (eGFR ≤60 ml/min/1.73 m2). When measuring the state of diastolic dysfunction of the right parts of the heart, a decrease in E/As well as an increase in the circulatory vascular resistance index and mean blood pressure were significantly higher in the first group of patients (where еGFR ≥6 ml/min/1.73 m2). After a course of treatment with t. carvedilol, based on basic treatment, normalization of endothelial function was determined, reflected in an increase in the concentration of stable metabolites of nitric oxide by 1.05 and 1.5 times (p&amp;lt;0.05) in the biological fluid, respectively, in the first and second groups. In the dynamics of the course of therapy in groups of patients with 75% and 35% decrease in lung ventilation capacity, mean pulmonary arterial pressure decreased by 18.1 and 14.3%, respectively, and the hemodynamic resistance index decreased by 7.9% and 5.7% in parallel (p&amp;lt;0.05). Conclusion When monitoring the functional state of central and renal hemodynamics and ventilation-perfusion function of the bronchopulmonary system after complex treatment with carvedilol, a long-term hypotensive effect, a decrease in endothelial dysfunction, respectively, and an improvement in central and renal hemodynamics were determined.

Arterial stiffness and endothelial function in the long-term period after a coronavirus disease 2019

Aim. To assess endothelial function and arterial stiffness over time in patients after hospitalization with coronavirus disease 2019 (COVID-19) and compare them with a control group.Material and methods. A total of 53 patients over 18 years of age were hospitalized for COVID-19 in June — August 2021 was examined at two visits: the first — 10-16 months, the second — 14-23 months after discharge from the hospital. Control group included 53 patients from the ESSE-RF epidemiological study of a St. Petersburg population who did not have COVID-19, selected by sex, status of smoking, hypertension and type 2 diabetes. Endothelial function was assessed by the levels of vascular cell adhesion molecule 1 (VCAM-1) and von Willebrand factor (vWF) in plasma and the reactive hyperemia index (lnRHI) on the EndoPAT 2000 system. Carotid-femoral pulse wave velocity (cfPWV) was determined using the SphygmoCor device, while cardio-ankle vascular index (CAVI) and ankle-brachial index (ABI) — using the VaSera device.Results. The prevalence of endothelial vasomotor function disorders at the first and second visits in the active group did not differ significantly as follows: lnRHI £0,51 — 21% and 21%, cfPWV &gt;10 m/s — 17% and 14%, and SLSI &gt;9 — 28% and 34%, respectively. Plasma VCAM-1 levels were significantly higher during hospitalization than at the first and second visits — no differences were found between visits. The levels of lnRHI, vWF, cfPWV, CAVI, ABI at the first and second visits did not differ significantly. Post-COVID-19 patients differed from the control group only by a significantly higher ABI level at the second visit. According to the analysis of covariance, COVID-19 is associated with a CAVI increase at the first visit, as well as with an increase in ABI at both visits.Conclusion. The 1,5-2-year follow-up of patients after COVID-19, which required hospitalization, showed a decrease in the plasma endothelial dysfunction parameter VCAM-1. There is no changes in endothelial function and arterial stiffness over a period of time from 10-16 months to 14-23 months after hospitalization with COVID-19.

Abstract 1086: Singing Improves Vascular Function

Introduction: Singing is a physical activity with less reliance on skeletal muscle and more dependence on the diaphragm and cardiorespiratory systems. Unlike traditional exercise, the impact of singing on vascular health has not been studied. We hypothesized that older patients with known coronary artery disease (CAD) would have a favorable improvement in vascular endothelial function after 30 minutes of singing. Methods: Adult subjects with known CAD were recruited from cardiology clinics to participate in two singing sessions 30 minutes each and one control (rest period) session 2 to 7 days apart, according to a randomized, controlled, single-blind, crossover design. The two singing intervention sessions were (1) a pre-recorded video with a voice professor directing a ‘patient’ singing and (2) live singing coaching with a music therapist. Microvascular function was measured with peripheral arterial tonometry (PAT) before and after singing and expressed as Framingham reactive hyperemia index (fRHI). Macrovascular function was measured with brachial artery flow-mediated dilation. Cross-over treatment estimates of video, coaching, and control sessions were obtained with unbalanced ANOVA including the following variables: subject, the order of their visit, treatment, and its carry-over. Results: Sixty-five subjects (40% women, mean age 68±7) with CAD completed the study. Comorbidities included type 2 diabetes (29%), hypertension (75%), hyperlipidemia (85%), heart failure (19%), and self-reported physical or orthopedic limitations (54%). Compared to the control visit, there was a 26.5% (SE11.1%, p=0.0192) increase in fRHI in the video visit and a 17.3% (SE 10.7%, p=0.1081) increase in fRHI in the coaching visit. There was a small carryover effect with the video visit. There was no change in macrovascular endothelial function across the three different visits. Conclusions: Thirty minutes of singing improved microvascular endothelial function but not macrovascular endothelial function, in older patients with known CAD. This represents a potential biologic mechanism by which singing can benefit the cardiovascular system. Future studies should explore the sustained vascular adaptation to singing over weeks to months of singing.

Gastric Cancer Mesenchymal Stem Cells Trigger Endothelial Cell Functional Changes to Promote Cancer Progression.

Our previous studies have highlighted the pivotal role of gastric cancer mesenchymal stem cells (GCMSCs) in tumor initiation, progression, and metastasis. In parallel, it is well-documented that endothelial cells (ECs) undergo functional alterations in response to challenging tumor microenvironment. This study aims to elucidate whether functional changes in ECs might be induced by GCMSCs and thus influence cancer progression. Cell proliferation was assessed through CCK-8 and colony formation assays, while cell migration and invasion capabilities were evaluated by wound-healing and Transwell assays. Immunohistochemistry was employed to examine protein distribution and expression levels. Additionally, quantitative analysis of protein and mRNA expression was carried out through Western blotting and qRT-PCR respectively, with gene knockdown achieved using siRNA. Our findings revealed that GCMSCs effectively stimulate cell proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs), both in vitro and in vivo. GCMSCs promote the migration and invasion of gastric cancer cells by inducing the expression of Slit2 in HUVECs. Notably, the inhibition of phosphorylated AKT partially mitigates the aforementioned effects. In conclusion, GCMSCs may exert regulatory control over Slit2 expression in ECs via the AKT signaling pathway, thereby inducing functional changes in ECs that promote tumor progression.

Impact of Insulin-Induced Relative Hypoglycemia on Vascular Insulin Sensitivity and Central Hemodynamics in Prediabetes.

Relative hypoglycemia (RH) is linked to sympathetic responses that can alter vascular function in individuals with type 2 diabetes. However, less is known about the role of RH on hemodynamics or metabolic insulin sensitivity in prediabetes. Determine if RH alters peripheral endothelial function or central hemodynamics to a greater extent in those with prediabetes (PD) versus normoglycemia (NG). Seventy adults with obesity were classified using ADA criteria as PD (n=34 (28F); HbA1c=6.02±0.1%) or NG (n=36 (30F); HbA1c=5.4±0.0%). Brachial artery endothelial function, skeletal muscle capillary perfusion, and aortic waveforms were assessed at 0 and 120min of a euglycemic clamp (40 mU/m2/min, 90 mg/dl). Plasma nitrate/nitrite and endothelin-1 (ET-1) were measured as surrogates of nitric oxide-mediated vasodilation and vasoconstriction, respectively. RH was defined as the drop in glucose (%) from fasting to clamp steady state. There were no differences in age, weight, or VO2max between groups. PD had higher HbA1c (P<0.01) and a greater drop in glucose in response to insulin (14 vs. 8%; P=0.03). Further, heart rate (HR) increased in NG compared to PD (P<0.01), while forward wave (Pf) decreased in PD (P=0.04). Insulin also tended to reduce arterial stiffness (cfPWV) in NG versus PD (P=0.07), despite similar increases in pre-occlusion diameter (P=0.02), blood flow (P=0.02), and lower augmentation index (AIx75) (P≤0.05). Compared with NG, insulin-induced RH corresponded with a blunted rise in HR and drop in Pf during insulin infusion in adults with PD, independent of changes in peripheral endothelial function.

Modulation of expression of Connexins 37, 40 and 43 in endothelial cells in culture.

Connexin (Cx) 37, 40, and 43 are implicated in vascular function, specifically in the electrical coupling of endothelial cells and vascular smooth-muscle cells. In the present study, we investigated whether factors implicated in vascular dysfunction can modulate the gene expression of Cx37, Cx40, and Cx43 and whether this is associated with changes in endothelial layer barrier function in human microvascular endothelial cells (HMEC-1). First, HMEC-1 were subjected to stimuli for 4 and 8h. We tested their responses to DETA-NONOate, H2O2, high glucose, and angiotensin II, none of which relevantly affected the transcription of the connexin genes. Next, we tested inflammatory factors IL-6, interferon gamma (IFNγ), and TNFα. IFNγ (10ng/mL) consistently induced Cx40 expression at 4 and 8 h to 10-20-fold when corrected for the control. TNFα and IL-6 resulted in small but significant depressions of Cx37 expression at 4h. Two JAK inhibitors, epigallocatechin-3-gallate (EGCG) (100-250μM) and AG490 (100-250μM), dose-dependently inhibited the induction of Cx40 expression by IFNγ. Subsequently, HMEC-1 were subjected to 10ng/mL IFNγ for 60h, and intercellular and transcellular impedance was monitored by electric cell-substrate impedance sensing (ECIS). In response to IFNγ, junctional-barrier impedance increased more than cellular-barrier impedance; this was prevented by AG490 (5μM). In conclusion, IFNγ can strongly induce Cx40 expression and modify the barrier properties of the endothelial cell membrane through the JAK/STAT pathway. Moreover, the Cx37, Cx40, and Cx43 expression in endothelial cells is stable and, apart from IFNγ, not affected by a number of factors implicated in endothelial dysfunction and vascular diseases.

Long-Term Microvascular Changes in Multisystem Inflammatory Syndrome in Children

This case-control study investigates changes in microcirculation and endothelial function in the acute phase of multisystem inflammatory syndrome in children and 3 to 6 months after onset.

Arterial structure and function in patients with hemoblastoses before and after high-dose chemotherapy and autologous hematopoietic stem cell transplantation

Background: High dose chemotherapy (HDCT) preceding autologous hematopoietic stem cell transplantation (autoSCT) can be toxic for cardiovascular system, which can be mediated with the development of endothelial dysfunction. No studies on the assessment of arterial stiffness and endothelial function after HDCT and autoSCT have been performed before.&#x0D; Aim: To evaluate endothelial function and arterial rigidity parameters by photoplethysmography in patient candidates for HDCT with autoSCT, to identify associated factors and to analyze changes of these parameters over time after HDCT and autoSCT.&#x0D; Materials and methods: In this cohort prospective observational study in 71 patients with verified hemoblastosis (mean age 43.8 ± 12.6 years) we assessed endothelial function and stiffness by photoplethysmography (AngioScan-01, Russia) before and after HDCT with autoSCT. Thirty two (32, 45%) patients had multiple myeloma (ММ), 39 (55%), lymphoproliferative disorders (LPD). We measured the stiffness index (SI), reflection index (RI), augmentation index normalized by heart rate of 75 beats per minute (AIp75) and performed the occlusion test with measurement of occlusion index (ОI) and phase shift (PS).&#x0D; Results: Mean RI in the total study group before HDCT with autoSCT was increased to RI 34.9% [24.5; 50.6], OI decreased to OI 1.5 [1.25; 1.80], and PS module decreased to PS 6.7 ms [3.9; 8.9]. After HDCT with autoSCT the PS module increased to 8.4 ms [5.0; 12.4] (p = 0.001) and OI increased to 1.7 [1.3; 2.2] (p = 0,007), which indicates an improvement in endothelial function.&#x0D; Changes in other parameters of arterial function were non-significant. We also analyzed a selected group of the patients with MM who had higher cardiovascular risk, compared to the LPD patients: they were older (53 vs 36.1 years; p 0.001), had higher rates of arterial hypertension (p 0.001) and diabetes mellitus (p = 0.048). Compared to the LPD patients, the MM patients had higher baseline values of SI (7.5 m/s [7.3; 7.9]), RI (42.9% [32.1; 53.6]), and AIp75 (6.3% [-1.65; 13.8]), indicating higher vascular stiffness. They also had lower PS module values (5.0 ms [2.1; 8.5]). The LPD patients had been more frequently treated with anthracyclines (p 0.001) and radiation (p = 0.002). After HDCT with autoSCT, they had a higher increment of OI, namely, from 1.4 [1.3; 1.8] to 1.7 [1.4; 2.1] (p = 0.003).&#x0D; Conclusion: This study was the first to show a high rate of endothelial dysfunction and vascular stiffness abnormalities in patients with hemoblastoses who were candidates for HDCT with autoSCT. After HDCT with autoSCT, changes of endothelial function and stiffness were multidirectional. Despite a significant improvement, endothelial function parameters were not normalized. We were unable to find any predictors of the abnormalities. Thus, the identified baseline abnormalities in stiffness and endothelial function cannot be a contraindication to HDCT with autoSCT.

Non-hyperaemic coronary flow velocity acceleration indices correlate with hyperaemic microvascular resistance in patients with INOCA

Abstract Background Coronary microvascular dysfunction (CMD) is associated with an overall worse prognosis. While the diagnosis and endo-typing of CMD currently rely on hyperaemic physiological indices, the search for accurate non-hyperaemic techniques continues. Flow velocity acceleration pattern is mechanistically associated with changes in shear stress, endothelial function, arterial stiffness and pressure in pulsatile flow systems (1-3). Purpose We aim to interrogate whether resting flow velocity acceleration indices correlate with hyperaemic microvascular resistance (HMR) in patients with Ischemia and no obstructive coronary artery disease (INOCA). Methods In 21 Patients with INOCA (all of whom had presented with typical angina pectoris, had no significant epicardial stenoses but positive myocardial perfusion scan test for ischemia) invasive physiological assessment was performed by means of intracoronary Doppler. Hyperaemia was induced with intracoronary adenosine administration. Coronary flow reserve (CFR) and HMR were calculated per their definitions. Flow velocity acceleration indices were derived from the first derivative of the averaged resting flow velocity waveforms with respect to time. We have defined 6 wave peaks of interest in all patients (peak diastolic acceleration (initial prominent peak with ventricular relaxation, referred as A), early diastolic deceleration (B), early re-acceleration wave (C), peak presystolic deceleration (seen just before initial systolic acceleration peak, J), initial systolic acceleration peak (X) and pre-diastolic deceleration nadir (Z)) and calculated the ratios between them as well as adjusted them with respect to resting mean flow velocity (Figure 1). Results The mean age was 59 ± 8 years and the majority of the study group was female (%81). Cardiovascular risk factors were common amongst the study group.All patients had CFR &amp;lt; 2.5. Mean CFR and HMR were 2.05 ± 0.32 and 2.20 ± 0.60 mmHg.cm.sec-1 respectively. Raw C peak magnitude was significantly correlated with APVh (rho:-0.457 p:0.037) and HMR (rho:0.612 p:0.004). Adjusting the C magnitudes with APVb at patient level yielded better correlations (APVh rho:-0.496 p:0.022 ; HMR:0.642 p:0.002). The ratio between diastolic reacceleration peak (C) and presystolic peak deceleration (J), C/J , adjusted with the APVb ((C/J)/APVb) showed the most pronounced correlation with HMR (rho: 0.758 p &amp;lt; 0.001) (unadjusted C/J – HMR rho: 0.718 p&amp;lt;0.001)(Figure 2). Conclusion(s) Acceleration characteristics of resting coronary flow velocity correlate with hyperaemic microvascular resistance indicating structurally impaired coronary microcirculation, hence their utilisation may aid developing non-hyperaemic physiological markers for coronary microvascular dysfunction in patients with INOCA.Derived Acceleration WaveformsCorrelations between HMR and C/J Ratio