Endothelial Vasodilator Research Articles

Shear stress-stimulated AMPK couples endothelial cell mechanics, metabolism, and vasodilation.

Endothelial cells respond to mechanical force by stimulating cellular signaling, but how these pathways are linked to elevations in cell metabolism and whether metabolism supports the mechanical response remains poorly understood. Here, we show that the application of force to endothelial cells stimulates VE-cadherin to activate liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis. VE-cadherin stimulated AMPK increases eNOS activity and localization to the plasma membrane, reinforcement of the actin cytoskeleton and cadherin adhesion complex, and glucose uptake. We present evidence for the increase in metabolism being necessary to fortify the adhesion complex, actin cytoskeleton, and cellular alignment. Together these data extend the paradigm for how mechanotransduction and metabolism are linked to include a connection to vasodilation, thereby providing new insight into how diseases involving contractile, metabolic, and vasodilatory disturbances arise.

HIV and cardiovascular risk: should we use other targets for cholesterol control? Brazilian data compared to major studies

Abstract In daily clinical practice, cardiologists are confronted with patients with HIV/AIDS and this population needs special attention due to their higher cardiovascular risk. Studies show an increase in cardiovascular disease (CVD) among people with HIV/AIDS and one of the main causes of death in this group. HIV is associated with dyslipidaemia and endothelial damage, which have been proposed as a cause of the increased risk of events, and HIV replication is a determining factor in endothelial dysfunction. With antiretroviral therapy (ART) there has been a reduction in morbidity and mortality from HIV/AIDS, however, several studies have shown an increase risk factors for CVD in this population, both in individuals on ART and those not on it. Two high-impact studies related to cardiovascular risk in the HIV population are Start and Smart. Studies are important for understanding this occurrence and its relationship with the presence of the virus and the use of antiretroviral therapy in this population. In view of the higher cardiovascular risk of these patients and the question of whether they deserve a different cholesterol target from other populations. Methods A retrospective, observational study was carried out on a sample of HIV patients from the Brazilian STD/AIDS Reference Centre (CRT), selected by lottery using their registration number, from 1 January 2011 to February 2023, aged over 18. 148 medical records were assessed and the following were collected population characteristics. Discussion: the CRT data were compared with the Start and Smart studies. The Reprieve study showed benefits earlier than expected with patients receiving a statin. An interim analysis revealed a 35 per cent reduction in serious adverse cardiovascular events in the statin group, leading to the placebo group stopping earlier. The viral load varied between the studies, with CRT having an average of 500,000 copies/ml, Start 12,759 copies/ml and Smart less than 400 copies/ml. Studies have associated HIV infection and higher viral loads with impaired endothelial function and vasodilation. Despite the data in the literature, all the patients with heart disease had undetected viral loads and CD4+ cell counts above 500 cells/mm³. Those with a high viral load in the study were not the ones with CVD. Conclusions In CRT, the percentage of primary events attributable to serious conditions unrelated to AIDS was 1.3 per cent. Analysing biomarkers could elucidate the effects of antiretroviral therapy on arterial disease. Another fact that probably justifies the low occurrence of cardiovascular and cerebral events in CRT is the multidisciplinary care given to patients, providing intensive primary and secondary prevention through counselling and follow-up. We suggest better control of cardiovascular risk factors with multi-professional intervention and more aggressive targets for the control of comorbidities.Characteristics and Cardiovascular risk

LDL-c/HDL-c Ratio and NADPH-Oxidase-2-Derived Oxidative Stress as Main Determinants of Microvascular Endothelial Function in Morbidly Obese Subjects.

The identification of obese subjects at higher risk for cardiovascular disease (CVD) is required. We aimed to characterize determinants of endothelial dysfunction, the initial step to CVD, in small omental arteries of visceral fat from obese subjects. The influences of analytical parameters and vascular oxidative stress mediated by NADPH-oxidase-2 (NOX2) on endothelial function were determined. Specimens were obtained from 51 obese subjects undergoing bariatric surgery and 14 non-obese subjects undergoing abdominal surgery. Obese subjects displayed reduced endothelial vasodilation to bradykinin (BK). Endothelial vasodilation (pEC50 for BK) among obese subjects was significantly and negatively associated with low-density lipoprotein cholesterol (LDL-c)/high-density lipoprotein cholesterol (HDL-c) ratio (r = -0.510, p = 0.0001) in both women and men, while other metabolic parameters and comorbidities failed to predict endothelial function. The vascular expression of NOX2 was upregulated in obese subjects and was related to decreased endothelial vasodilation (r = -0.529, p = 0.0006, n = 38) and increased oxidative stress (r = 0.783, p = 0.0044, n = 11) in arterial segments. High LDL-c/HDL-c (>2) and high NOX2 (above median) were independently associated with reduced endothelial function, but the presence of both conditions was related to a further impairment. Concomitant elevated LDL-c/HDL-c ratio and high vascular expression of NOX2 would exacerbate endothelial impairment in obesity and could reveal a deleterious profile for cardiovascular outcomes among obese subjects.

Methylglyoxal induces endothelial cell apoptosis and coronary microvascular dysfunction through regulating AR-cPLA2 signaling

ObjectiveSince diabetic patients with coronary microvascular dysfunction (CMD) exhibit high cardiac mortality and women have higher prevalence of non-obstructive coronary artery disease than men, we tried to expand the limited understanding about the etiology and the sex difference of diabetic CMD. Approach and resultsAccumulated methylglyoxal (MGO) due to diabetes promotes vascular damage and it was used for mimicking diabetic status. Flow cytometry analysis and isometric tension measurement were performed to evaluate coronary artery endothelial injury. MGO induced apoptosis of coronary endothelial cells, accompanied by downregulation of androgen receptor (AR). Lentivirus-mediated stable expression of AR in coronary endothelial cells increased anti-apoptotic Bcl-2 expression and attenuated MGO-induced cell apoptosis. cPLA2 activation was the downstream of AR downregulation by MGO treatment. Moreover, MGO also activated cPLA2 rapidly to impair endothelium-dependent vasodilation of coronary arteries from mice. Reactive oxygen species (ROS) overproduction was demonstrated to account for MGO-mediated cPLA2 activation and endothelial dysfunction. Importantly, AR blockade increased endothelial ROS production whereas AR activation protected coronary artery endothelial vasodilatory function from the MGO-induced injury. Although galectin-3 upregulation was confirmed by siRNA knockdown in endothelial cells not to participate in MGO-induced endothelial apoptosis, pharmacological inhibitor of galectin-3 further enhanced MGO-triggered ROS generation and coronary artery endothelial impairment. ConclusionsOur data proposed the AR downregulation-ROS overproduction-cPLA2 activation pathway as one of the mechanisms underlying diabetic CMD and postulated a possible reason for the sex difference of CMD-related angina. Meanwhile, MGO-induced galectin-3 activation played a compensatory role against coronary endothelial dysfunction.

TMAO Impairs Mouse Aortic Vasodilation by Inhibiting TRPV4 Channels in Endothelial Cells.

Trimethylamine oxide (TMAO) is an intestinal flora metabolite associated with risk of cardiovascular diseases. Transient receptor potential vanilloid 4 (TRPV4) is a Ca2+-permeable ion channel that is essential for vasodilation and endothelial function. Currently, there are few studies on the effect of TMAO on TRPV4 channels. In the present study, Ca2+ imaging of vascular tissue showed that TMAO inhibited TRPV4-mediated Ca2+ influx into aortic endothelial cells in a dose-dependent manner. Furthermore, a whole-cell patch clamp assay showed that TMAO blocked TRPV4-mediated cation currents. Notably, results of aortic vascular tension measurement showed that TMAO impaired endothelium-dependent vasodilation in mouse aortic vessels through the TRPV4-NO pathway. Our results indicated that TMAO inhibited Ca2+ entry in endothelial cells and impaired vasodilation through the TRPV4-NO pathway in mice. These results provide scientific evidence for novel pathogenic mechanisms underlying the role of TMAO in cardiovascular disease.

(098) LOW INTENSITY SHOCKWAVE THERAPY FOR WOMEN WITH SEXUAL DYSFUNCTION

Abstract Introduction Low intensity shockwave therapy (LiSWT) has been used to treat sexual dysfunction by inducing genital tissue mechanotransduction. Mechanotransduction is the ability of a cell to actively convert contraction/expansion mechanical stimuli induced by exposure to the shockwave energy into biochemical signals with physiological effects including synthesis of nitic oxide, upregulation of vascular endothelial growth factors, recruitment of endothelial progenitor cells, vasodilation, and expression of tumor necrosis factor alpha mRNA with anti-inflammatory activity. The greater the shockwave energy absorbed in genital tissues, the greater the opportunity for mechanotransduction physiologic effects to occur and improve sexual function. Therefore, effectiveness of LiSWT depends, in part, on applied energy (mJ/mm2) and number of applications (total shocks). In 2019, our sexual medicine clinic began utilizing the SoftWave (Urogold 100™) LiSWT device, FDA cleared for pain amelioration, connective tissue activation, wound healing, and improved blood flow, to treat individuals with vulvas with sexual dysfunction. Objective To review the various sexual health concerns in individuals with vulvas effectively treated by LiSWT. Methods A chart review was performed of individuals with vulvas with various sexual dysfunctions, including genital pain and genito-pelvic dysesthesia (GPD), who received LiSWT between April 2019 and June 2023. In general, 2400 shocks were applied at energy flux density 0.05-0.08 mJ/mm2, Hz = 3, membrane pressure = 1. The Patient Global Impression of Improvement (PGI-I) was used to assess post-LiSWT outcome; improvement was positive if the post-LiSWT PGI-I ranged from 1-3. Results 189 women, mean age 32 (range 18–67) years, with sexual dysfunction underwent LiSWT treatments in the 38 months. 18 women with neuroproliferative vestibulodynia (NPV) who underwent vestibulectomy received 3-6 post-operative vestibular LiSWT to reduce post-operative pain and improve wound healing; 83% reported improved PGI-I. 24 patients with hormone-mediated vestibulodynia who elected not to use hormone treatment, underwent vestibular LiSWT; 54% reported improved PGI-I. 25 menopausal patients with persistent symptoms of Genito-Urinary Syndrome of Menopause (GSM) received multiple vestibular LiSWT treatments; 64% improved PGI-I, including reduction of urinary incontinence. 36 women with PGAD/GPD from lumbosacral annular tear-and/or Tarlov cyst-induced sacral radiculopathy who were not candidates for minimally invasive spine surgery or continued to have symptoms after recovering from spine surgery, underwent multiple treatments of lumbosacral spine LiSWT; 58% reported improved PGI-I. 86 patients with neuroproliferative vestibulodynia (NPV) underwent 2-3 pre-operative sessions of vestibular LiSWT immediately prior to complete subepithelial vestibulectomy surgery; they used significantly fewer opioids post-op than those without pre-operative LiSWT based on historical data prior to 2019. All patients received multiple LiSWT sessions to maximize mechanotransduction effects on genital tissues. There were no significant adverse events noted with LiSWT use. Conclusions Multiple LiSWT sessions are utilized in individuals with vulvas with sexual dysfunction to maximize mechanotransduction. LiSWT is associated with improved sexual health symptoms ranging from 54% - 75%, not associated with any side effects. More research is needed regarding the role of LiSWT for management of various sexual dysfunctions. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Softwave TRT.

Improving Cerebrovascular Reactivity After Carotid Endarterectomy Is Not Accompanied by Improvement in Endothelial Vasodilator Function (P10-5.024)

Improving Cerebrovascular Reactivity After Carotid Endarterectomy Is Not Accompanied by Improvement in Endothelial Vasodilator Function (P10-5.024)

Endothelial-Specific Reduction in Arf6 Impairs Insulin-Stimulated Vasodilation and Skeletal Muscle Blood Flow Resulting in Systemic Insulin Resistance in Mice.

Much of what we know about insulin resistance is based on studies from metabolically active tissues such as the liver, adipose tissue, and skeletal muscle. Emerging evidence suggests that the vascular endothelium plays a crucial role in systemic insulin resistance; however, the underlying mechanisms remain incompletely understood. Arf6 (ADP ribosylation factor 6) is a small GTPase that plays a critical role in endothelial cell function. Here, we tested the hypothesis that the deletion of endothelial Arf6 will result in systemic insulin resistance. We used mouse models of constitutive endothelial cell-specific Arf6 deletion (Arf6f/- Tie2Cre+) and tamoxifen-inducible Arf6 knockout (Arf6f/f Cdh5CreER+). Endothelium-dependent vasodilation was assessed using pressure myography. Metabolic function was assessed using a battery of metabolic assessments including glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps. We used a fluorescence microsphere-based technique to measure tissue blood flow. Skeletal muscle capillary density was assessed using intravital microscopy. Endothelial Arf6 deletion impaired insulin-stimulated vasodilation in white adipose tissue and skeletal muscle feed arteries. The impairment in vasodilation was primarily due to attenuated insulin-stimulated nitric oxide bioavailability but independent of altered acetylcholine-mediated or sodium nitroprusside-mediated vasodilation. Endothelial cell-specific deletion of Arf6 also resulted in systematic insulin resistance in normal chow-fed mice and glucose intolerance in high-fat diet-fed obese mice. The underlying mechanisms of glucose intolerance were reductions in insulin-stimulated blood flow and glucose uptake in the skeletal muscle and were independent of changes in capillary density or vascular permeability. Results from this study support the conclusion that endothelial Arf6 signaling is essential for maintaining insulin sensitivity. Reduced expression of endothelial Arf6 impairs insulin-mediated vasodilation and results in systemic insulin resistance. These results have therapeutic implications for diseases that are associated with endothelial cell dysfunction and insulin resistance such as diabetes.

Abstract P197: Dietary Quality Determined by Healthy Eating Index-2015 and Endothelial Function in Healthy Adults

The Healthy Eating Index (HEI) is a measure of diet quality based on Dietary Guidelines for Americans and developed in collaboration with the US Department of Health and Human Services and the US Department of Agriculture. Clinical interest in HEI has increased due to its association with obesity, inflammatory biomarkers and risk of coronary heart disease and stroke. Indeed, higher HEI-2015 score has been linked with reduced cardiovascular risk, morbidity, and mortality. Endothelial dysfunction, particularly impaired endothelium-dependent vasodilation, is a central etiological factor underlying cardiovascular risk and events. We and others have previously demonstrated that diets high in saturated fat and other proatherogenic diets are associated with endothelial vasodilator dysfunction. It is currently unknown whether HEI-2015 dietary score is associated with endothelial function. If so, assessing dietary quality based on HEI-2015 may provide targeted nutritional guidance for enhancing vascular health and mitigating cardiovascular risk. The aim of this study was to determine whether HEI-2015 score is associated with endothelial vasodilator function in healthy adults. Using data from 4-day dietary records, HEI-2015 scores were determined in 103 adults (65 M/38 F; age 44-68 years) free of overt cardiometabolic disease. The HEI-2015 score is based on 13 components summed to yield a total score from 0 to 100; higher score representing higher diet quality. The adults were stratified by HEI-2015 score quartiles: Q1: HEI < 52.5 (n=25; 23 M/2 F); Q2: HEI 52.6-59.1 (n=26; 14 M/12 F); Q3: HEI 59.2-66.0 (n=26; 15 M/11 F); and Q4: HEI > 66.0 (n=26; 13 M/13 F). Endothelium-dependent vasodilation was determined by forearm blood flow (FBF) (via plethysmography) responses to intra-arterial infusion of acetylcholine (ACh: 4.0, 8.0, and 16.0 μg/100 mL tissue/min) and sodium nitroprusside (NTP: 1.0, 2.0, and 4.0 μg/100 mL tissue/min). There were no significant differences in endothelium-dependent vasodilation across the HEI-2015 score quartiles. FBF blood responses to ACh were remarkably similar between Q1 (5.1±0.2 to 13.0±0.7 mL/100 mL tissue/min), Q2 (4.3±0.2 to 12.1±0.7 mL/100 mL tissue/min), Q3 (4.4±0.2 to 13.0±0.7 mL/100 mL tissue/min) and Q4 (4.5±0.2 to 14.4±0.6 mL/100 mL tissue/min). Moreover, HEI scores were not significantly associated with the vasodilator response to either ACh (r=0.15, P=0.13) or NTP (r=-0.04; P=0.72). In summary, although diet quality determined by HEI-2015 score has been shown to be associated with increased risk of cardiovascular disease and events, HEI-2015 was not associated endothelial function in mid-life and older adults. Given the established experimental and pathophysiological evidence linking between diet, endothelial vasodilator function and cardiovascular risk, HEI-2015 score is not a sensitive dietary indicator/biomarker of vascular function.

Clinical Biomarkers of Acute Vaso-Occlusive Sickle Cell Crisis.

It is known that an inherited blood condition called sickle cell disease (SCD) is a result of one gene. A number of blood and urine biomarkers have been determined in association with lab and clinical history for SCD patients. SCD has numerous interacting pathways associated with it, which have been identified by biomarkers. These mechanisms consist of some examples, such as endothelial vasodilation response, hypercoagulability, hemolysis, inflammation, oxidative stress, vascular dysfunction, and reperfusion injury among others. To effectively manage SCD, a comprehensive panel of validated blood and urine biomarkers must be established. Despite its monogenic inheritance, the complex nature of the SCD phenotype has impeded progress in its treatment. However, significant strides have been made in clinical biotechnology, paving the way for potential breakthroughs. In SCD, a panel of verified blood and urine biomarkers must be established, however. Despite monogenic inheritance, the great complexity of the SCD phenotype has hindered progress in its management. With few exceptions, clinical biomarkers of illness severity have been found through epidemiological investigations; nevertheless, systematic integration of these biomarkers into clinical treatment algorithms has not occurred. Furthermore, sickle cell crisis, the primary acute consequence of SCD, has been difficult to diagnose with the biomarkers now in use. Inadequate care and a lack of appropriate outcome measures for clinical research are the consequences of these diagnostic constraints. A new chapter in SCD customized treatment has begun with recent advancements in molecular and imaging diagnostics. Strategies in precision medicine are especially relevant now that molecular therapies are within reach. The significance of biochemical indicators linked to clinical manifestation and sub-phenotype identification in SCD is reviewed in this research.

Testosterone modulates vasodilation in mesenteric arteries of hypertensive rats

AimsTo evaluate the effects of testosterone on endothelium-dependent vasodilation and oxidative stress in mesenteric resistance arteries. Main methodsSpontaneously hypertensive rats (SHR), aged 8 to 10 weeks, were divided into four groups: intact (SHAM), intact treated with testosterone (TTO; 3 mg/kg/day) via subcutaneous route (s.c.), intact treated with testosterone and anastrozole [aromatase enzyme inhibitor (TTO + ANA; 0.1 mg/kg/day, s.c.)] and intact treated with testosterone and finasteride [5 α-reductase enzyme inhibitor (TTO + FIN; 5 mg/kg/day, s.c.)] for four weeks. Concentration-response curves to acetylcholine (ACh, 0.1 nmol/L - 10 μmol/L) were obtained in mesenteric resistance arteries previously contracted with phenylephrine (PE, 3 μmol/L), before and after the use of selective inhibitors. Reactive oxygen species (ROS) levels were assessed in the vessels and the endothelium analyzed by scanning electron microscopy. Key findingsTTO group showed a lower participation of nitric oxide (NO), increased oxidative stress, and participation of prostanoids and endothelium-dependent hyperpolarization (EDH), possibly to maintain the vasodilator response. Lower participation of NO and prostanoids, combined to an increased participation of EDH, were observed in the TTO + ANA group, in addition to higher levels of ROS and altered endothelial morphology. The vasodilation to ACh was impaired in TTO + FIN, along increased participation of NO, reduction of prostanoids, and greater EDH-dependent vasodilation. SignificanceTestosterone contributes to endothelial vasodilation by enhancing EDH through an increased participation of epoxyeicosatrienoic acids. While the decrease in NO appears to involve the participation of dihydrotestosterone, 17 β-estradiol seems to stimulate the action of the NO pathway and prostanoids.

A phase Ib/II study of atezolizumab plus tivozanib in pancreatic, gallbladder, and bile duct malignancies.

TPS715 Background: Checkpoint inhibitor therapy represents a significant advance in cancer care however it is not an effective intervention in the treatment of several immunologically cold tumors including pancreatic, gallbladder, and bile duct malignancies where checkpoint inhibitors have produced objective response rates ranging from 0-6%. VEGF is thought to play a key role in modulating the anti-tumor immune response as it is secreted by tumors and leads to endothelial cell proliferation, vascular permeability, and vasodilation. This in turn leads to the development of an abnormal vasculature with excessive permeability and poor blood flow, thus limiting immune surveillance. In addition, VEGF inhibits dendritic cell differentiation, limiting the presentation of tumor antigens to CD4 and CD8 T cells. Through the inhibition of VEGF, it may be possible to potentiate the effect of immune checkpoint blockade. Combined use of a VEGF receptor tyrosine kinase inhibitor (TKI) and checkpoint inhibitor is already standard of care in advanced kidney and cervical cancers. Methods: This is a single institution, single arm, open-label phase Ib/II study with the co-primary endpoints of safety and efficacy of the combination of the VEGF receptor TKI tivozanib and checkpoint inhibitor atezolizumab. Eligible patients will include those with pancreatic, gallbladder, and bile duct cancers, as well as well-differentiated grade 2 and 3 neuroendocrine tumors, ovarian and vulvar cancer, soft tissue sarcoma, castrate resistant prostate cancer, and HER2 positive hormone receptor negative breast cancer, that is metastatic and progressed on at least one line of therapy. Key exclusion criteria will include patients with known mismatch repair deficiency, microsatellite instability, or high tumor mutational burden. The phase Ib portion will assess the safety profile of the combination of tivozanib and atezolizumab with a potential dose de-escalation of tivozanib using a 3+3 study design. Three patients will be treated at the dose of tivozanib 1.34 mg per day (dose level 0) for 21 days of each 28-day cycle and atezolizumab 1680 mg on day 1 of every 28-day cycle. If one dose limiting toxicity (DLT) is found then 3 more patients will be enrolled at dose level 0. If >1 DLT occurs in the first 3 patients or >1 DLT in the first 6, another 3+3 study will begin at dose level -1 (0.89 mg of tivozantib). If 1 DLT occurs in these 3 patients at dose level -1 then another 3 will be enrolled at this dose. The study will be stopped for toxicity if there is >1 DLT in the first 3 patients at dose level -1 or if there are >1 DLT in the 6 patients at dose level -1. The phase II portion will enroll up to 26 patients using the dose of tivozanib found to be safe in the Ib portion. Disease response assessment every 12 weeks with CT Chest, Abdomen, and Pelvis via RECIST 1.1. Treatment will continue until progression or intolerance. Clinical trial information: NCT05000294 .

Endothelial and exercise vasodilation are reduced in postmenopausal females with obesity versus lean and overweight.

Obesity (OB) is highly prevalent in females after menopause, especially visceral adipose tissue (VAT) accumulation which contributes to endothelial dysfunction. The endothelium assists in regulating blood flow (BF) during exercise and is attenuated in females with OB. The purpose of this study was to examine upper and lower limb flow-mediated dilation (FMD) and BF regulation during graded low-intensity submaximal exercises in postmenopausal females with BMI in the lean (LN), overweight (OW) and OB categories. Participants were grouped by body mass index (BMI) into LN (BMI 18.5-24.9 kg/m2; n = 11), OW (BMI 25.0-29.9 kg/m2; n = 15), and OB (BMI 30.0-39.9 kg/m2; n = 13). FMD of the brachial (BA-FMD) and superficial femoral arteries (FA-FMD) were assessed. Subsequently, BF and vascular conductance (VC) in the upper (BA-BF and BA-VC) and lower limbs (FA-BF and FA-VC) were measured during separate 3-stage incremental rhythmic handgrip and plantarflexion exercises. Significantly lower FA-FMD (P < 0.05) were seen in OB than LN and OW groups with no differences in BA-FMD. Increases in FA-BF and FA-VC were attenuated during the last stage of plantarflexion exercise at 30% of 1RM in OB (both P < 0.001) compared to LN and OW, while upper-body exercise vasodilation was unchanged. FA-BF and FA-VC during plantarflexion exercise were correlated to FA-FMD (FA-BF: r = 0.423, P = 0.007, FA-VC: r = 0.367, P = 0.021) and BMI (FA-BF: r = -0.386, P = 0.015, FA-VC: r = -0.456, P = 0.004). Postmenopausal females with OB have reduced lower-limb endothelial and exercise vasodilator function during submaximal dynamic plantarflexion exercise compared to LN and OW. Our findings indicate that obesity may predict diminished leg endothelial function, BF and VC during exercise in postmenopausal females.

Walnuts for the eye and vision

The increase in lifespan with the consequent expansion of the aging of the world population has become an important challenge for public health. In recent decades, there has been a progressive increase in the incidence of debilitating diseases related to aging, including neurodegenerative disorders and eye diseases. Oxidative stress and inflammation are believed to play a critical role in several eye disorders, such as age‐related macular degeneration (AMD), diabetic retinopathy (DR), and cataracts, the leading causes of visual loss and blindness worldwide. Neurodegenerative events were also related to AMD and DR.Nutrients such as n‐3 polyunsaturated fatty acids (n‐3 PUFA) and antioxidants, specifically polyphenols, carotenoids, and vitamins C and E, may play a role in preventing both cognitive decline and retinal degenerative processes. Nuts have been described as a “superfood”, containing a notable variety of natural components that may have additive and/or synergistic properties for health and may prevent some pathologies. Nuts in general and walnuts in particular have a rich matrix of these bioactive components and through additive effects, have the potential to beneficially impact neuronal function in the brain and retina. Among different nuts, walnuts contain n‐3 PUFAs, specifically α‐linolenic acid (ALA; C18:3n‐3). It is believed that ALA may improve brain health indirectly through conversion to docosahexaenoic acid (DHA; C22:6n‐3), which has the ability to modulate brain plasticity and counteracts neuroinflammation in experimental studies. Other bioactive compounds in walnuts, such as arginine, tocopherols, folate, melatonin and polyphenols, also support neurological health and cognitive well‐being by modulating blood pressure, HDL function, glucoregulation, endothelial vasodilator function, oxidative status and vascular dysfunction. Polyphenols (including ellagitannins) have high antioxidant and prebiotic properties, which can regulate the gut microbiome, which is related to the increased risk of several inflammatory diseases. There is growing evidence that walnuts may contribute positively to eye disorders such as AMD, DR, and cataract prevention.

Over-representation analysis of angiogenic factors in immunosuppressive mechanisms in neoplasms and neurological conditions during COVID-19

BackgroundRecent studies emphasized the necessity to identify key (human) biological processes and pathways targeted by the Coronaviridae family of viruses, especially Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronavirus Disease (COVID-19) caused up to 33–55 % death rates in COVID-19 patients with malignant neoplasms and Alzheimer's disease. Given this scenario, we identified biological processes and pathways involved in various diseases which are most likely affected by COVID-19. MethodsThe COVID-19 DisGeNET data set (v4.0) contains the associations between various diseases and human genes known to interact with viruses from Coronaviridae family and were obtained from the IntAct Coronavirus data set annotated with DisGeNET data. We constructed the disease-gene network to identify genes that are involved in various comorbid diseased states. Communities from the disease-gene network were identified using Louvain method and functional enrichment through over-representation analysis methodology was used to discover significant biological processes and pathways shared between COVID-19 and other diseases. ResultThe COVID-19 DisGeNET data set (v4.0) comprised of 828 human genes and 10,473 diseases (including various phenotypes) that together constituted nodes in the disease-gene network. Each of the 70,210 edges connects a human gene with an associated disease. The top 10 genes linked to most number of diseases were VEGFA, BCL2, CTNNB1, ALB, COX2, AGT, HLA-A, HMOX1, FGF2 and COMT. The most vulnerable group of patients thus discovered had comorbid conditions such as carcinomas, malignant neoplasms and Alzheimer's disease. Finally, we identified 15 potentially useful biological processes and pathways for improved therapies. Vascular endothelial growth factor (VEGF) is the key mediator of angiogenesis in cancer. It is widely distributed in the brain and plays a crucial role in brain inflammation regulating the level of angiopoietins. With a degree of 1899, VEGFA was associated with maximum number of diseases in the disease-gene network. Previous studies have indicated that increased levels of VEGFA in the blood results in dyspnea, Pulmonary Edema (PE), Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). In case of COVID-19 patients with neoplasms and other neurological symptoms, our results indicate VEGFA as a therapeutic target for inflammation suppression. As VEGFs are known to disproportionately affect cancer patients, improving endothelial permeability and vasodilation with anti-VEGF therapy could lead to suppression of inflammation and also improve oxygenation. As an outcome of our study, we make case for clinical investigations towards anti-VEGF therapies for such comorbid conditions affected by COVID-19 for better therapeutic outcomes.

Unexplained recurrent pregnancy loss and markers of arterial vascular health: An experimental case-control study.

To investigate whether women with unexplained recurrent pregnancy loss have impaired arterial vascular health compared with controls, and to evaluate whether this is modifiable by exercise. Experimental case-control pilot study. University medical centre in the Netherlands. Twelve women with unexplained recurrent pregnancy loss, 11 nulliparous women and 19 primiparous women with a history of uncomplicated pregnancies. In all three groups we measured baseline characteristics, metabolic components and arterial vascular health, and repeated this in women with unexplained recurrent pregnancy loss after 1 month of protocolled and supervised cycle training. Differences in arterial vascular health between women with unexplained recurrent pregnancy loss and controls, and the effect of exercise on arterial vascular health in women with unexplained recurrent pregnancy loss. Women with unexplained recurrent pregnancy loss have a significantly increased carotid intima media thickness in comparison with both controls (both P < 0.01), a significantly decreased brachial endothelial dependent flow-mediated vasodilation in comparison with both controls (nulliparous: P < 0.01; primiparous: P = 0.05) and a significantly decreased femoral endothelial dependent flow-mediated vasodilation in comparison with primiparous women (P = 0.01). The endothelium independent glyceryl trinitrate response was similar in all groups. With 1 month of exercise, the carotid intima media thickness decreased significantly by 7% (P = 0.05) and the femoral FMD increased significantly by 10% (P = 0.01) in women with unexplained recurrent pregnancy loss. Women with unexplained recurrent pregnancy loss have an impaired vascular health in comparison with controls. This impaired arterial vascular health can be improved by exercise.

Pressure Building Against the Clock: The Impact of Circadian Misalignment on Blood Pressure.

Misalignment between the endogenous biological timing system and behavioral activities (i.e., sleep/wake, eating, activity) contributes to adverse cardiovascular health. In this review, we discuss the effects of recurring circadian misalignment on blood pressure regulation and the implications for hypertension development. Additionally, we highlight emerging therapeutic approaches designed to mitigate the negative cardiovascular consequences elicited by circadian disruption. Circadian misalignment elicited by work schedules that require individuals to be awake during the biological night (i.e., shift work) alters 24-h blood pressure rhythms. Mechanistically, circadian misalignment appears to alter blood pressure via changes in autonomic nervous system balance, variations to sodium retention, dysregulation of endothelial vasodilatory responsiveness, and activation of proinflammatory mechanisms. Recurring circadian misalignment produced by a mismatch in sleep timing on free days vs. work days (i.e., social jetlag) appears to have no direct effects on prevailing blood pressure levels in healthy adults; though, circadian disruptions resulting from social jetlag may increase the risk of hypertension through enhanced sympathetic activation and/or obesity. Furthermore, social jetlag assessment may be a useful metric in shift work populations where the magnitude of circadian misalignment may be greater than in the general population. Circadian misalignment promotes unfavorable changes to 24-h blood pressure rhythms, most notably in shift working populations. While light therapy, melatonin supplementation, and the timing of drug administration may improve cardiovascular outcomes, interventions designed to target the effects of circadian misalignment on blood pressure regulation are warranted.

Roles of endothelial and smooth muscle cell dysfunction and vasa vasorum in vasomotor disorders in ischemia with no obstructive coronary artery disease

Recently, the importance has emerged of ischemia with no obstructive coronary artery disease (INOCA), for which endothelial and vascular smooth muscle cell (VSMC) dysfunctions and alterations in coronary vasa vasorum are involved. Regarding endothelial vasodilator functions, both endothelium-derived nitric oxide and endothelium-derived hyperpolarizing factor play important roles in modulating vascular tone, especially in the microcirculation. Recent studies have suggested systemic endothelial dysfunction in INOCA. Regarding VSMC dysfunction, Rho-kinase has been identified as a key molecular mechanism of VSMC hyperconstriction in INOCA. Finally, recent advances of coronary imaging have demonstrated the important role of altered adventitial vasa vasorum functions in INOCA.

Treatment with Ligilactobacillus murinus lowers blood pressure and intestinal permeability in spontaneously hypertensive rats

One feature of hypertension is a microbial imbalance with increased intestinal permeability. In this study, we examined whether an alteration in the microbiota affects blood pressure and intestinal permeability in spontaneously hypertensive rats (SHRs). We performed a 16S metagenome analysis of feces from 10- to 15-week-old SHRs using a synthetic long-read sequencing approach, and found a candidate for the microbiome treatment, Ligilactobacillus murinus (L. murinus), that was robustly decreased. Oral administration of L. murinus to SHRs for 2 weeks significantly inhibited blood pressure elevation and improved endothelium-dependent vasodilation but did not attenuate enhanced vascular contraction in SHR mesenteric arteries. The proximal colon of SHRs exhibited increased intestinal permeability with decreased levels of the tight junction protein claudin 4, morphological changes such as decreased intestinal crypts and elevated TNF-α levels, which was reversed by treatment with L. murinus. Consistent with these intestinal phenotypes, plasma lipopolysaccharides levels were elevated in SHR but decreased following L. murinus administration. We concluded that oral administration of L. murinus to SHRs exerts protective effects on intestinal permeability via restoration of claudin 4 expression and reversal of morphologic disorder, which may improve low-grade endotoxemia and thus reduce development of hypertension via recovery of endothelial vasodilating functions.

Abstract 085: Monocytes-derived Cytokines Induce Endothelial Dysfunction In Primary Aldosteronism

Due to aldosterone excess and its pleotropic effects, patients with primary aldosteronism (PA) are exposed to high rates of cardiovascular events. Endothelial dysfunction is the first step in the development of vascular disease and monocytes are an important immune cell type inducing vascular damage. Therefore, we measured endothelial function between PA patients and healthy controls and analyzed the impact of monocytes-derived cyctokines on the development of endothelial dysfunction. Endothelial function was measured in 13 healthy controls, 42 PA patients before and in 22 patients 6 months after initiation of a specific treatment using flow mediated dilation method (FMD). Monocytes were isolated from 6 healthy individuals as well as from 8 PA patients before and treatment. Cytokine profile was measured by a Human Cytokine 17-plex Assay (Bio-rad). The effects of monocyte-derived cytokines on endothelial function were studied by wire myography in pre-constricted thoracic aortic pieces of healthy mice. FMD was significantly lower among PA patients compared to controls. Surgical or pharmacological treatment significantly improved endothelial function in PA patients. Monocytes from untreated patients with PA secreted significantly higher concentrations of the following cytokines and growth factors than healthy controls: G-CSF, IFN-γ, TNF-α, IL-6, IL-10, IL-8, IL-17, and MCP-1. Especially concentrations of IL-6 (388 (351-580)pg/ml vs. 36(4-268)pg/ml, p&lt;0.05) and TNF-α (95(48-135)pg/ml vs 17(5-41)pg/ml, p&lt;0.05) were much higher among PA patients. In pre-constricted murine aortas, 24 hours incubation of the secretome from untreated patients with PA induced an impaired endothelial vasodilation compared to the secretome of the controls. Interestingly, in comparison to untreated patients, treatment of PA not only reduced monocytes-derived cytokine levels, but also improved endothelial dysfunction in pre-constricted aortas incubated with the corresponding secretome. Endothelial function is impaired in PA. This impairment seem to be in part mediated by an increased release of pro-inflammatory cytokines from monocytes. PA treatment reduced the pro-inflammatory activity of monocytes and improved endothelial function.