Mechanisms Of Endothelial Dysfunction Research Articles

Correlation of Asymmetric Dimethylarginine With Podocytopathy Markers in Diabetic Kidney Disease Patients.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and podocytopathy is an early manifestation of DKD characterized by the urinary excretion of podocyte-specific proteins, such as nephrin and podocin. Asymmetric dimethylarginine (ADMA)-a biomarker of endothelial dysfunction-is associated with progressive kidney dysfunction. However, the mechanism of endothelial dysfunction in DKD progression is unclear. The aim of this study was to investigate the correlations of ADMA levels with nephrin, podocin, and the podocin:nephrin ratio (PNR) in DKD patients. A cross-sectional study of 41 DKD outpatients was performed in two hospitals in Jakarta from April-June 2023. The collected data included the subjects' characteristics, histories of disease and medication, and relevant laboratory data. Serum ADMA was measured using liquid chromatography, while urinary podocin and nephrin were measured using the enzyme-linked immunosorbent assay (ELISA) method. A correlation analysis was performed to evaluate the correlation of ADMA with nephrin, podocin, and PNR. Regression analysis was performed to determine confounding factors. The mean value of ADMA was 70.2 (SD 17.2) ng/mL, the median for nephrin was 65 (20-283 ng/mL), and the median of podocin was 0.505 (0.433-0.622) ng/mL. ADMA correlated significantly with nephrin (r = 0.353, p = 0.024) and PNR (r = -0.360, p = 0.021), but no correlation was found between ADMA and podocin (r = 0.133, p = 0.409). The multivariate analysis showed that body mass index was a confounding factor. This study revealed weak positive correlations between ADMA and urinary nephrin and between ADMA and PNR. No correlation was found between ADMA and urinary podocin.

The Interplay of HIV and Long COVID in Sub-Saharan Africa: Mechanisms of Endothelial Dysfunction.

Long COVID affects approximately 5million people in Africa. This disease is characterized by persistent symptoms or new onset of symptoms after an acute SARS-CoV-2 infection. Specifically, the most common symptoms include a range of cardiovascular problems such as chest pain, orthostatic intolerance, tachycardia, syncope, and uncontrolled hypertension. Importantly, these conditions appear to have endothelial dysfunction as the common denominator, which is often due to impaired nitric oxide (NO) mechanisms. This review discusses the role of mechanisms contributing to endothelial dysfunction in Long COVID, particularly in people living with HIV. Recent studies have reported that increased inflammation and oxidative stress, frequently observed in Long COVID, may contribute to NO dysfunction, ultimately leading to decreased vascular reactivity. These mechanisms have also been reported in people living with HIV. In regions like Africa, where HIV infection is still a major public health challenge with a prevalence of approximately 26million people in 2022. Specifically, endothelial dysfunction has been reported as a major mechanism that appears to contribute to cardiovascular diseases and the intersection with Long COVID mechanisms is of particular concern. Further, it is well established that this population is more likely to develop Long COVID following infection with SARS-CoV-2. Therefore, concomitant infection with SARS-CoV-2 may lead to accelerated cardiovascular disease. We outline the details of the worsening health problems caused by Long COVID, which exacerbate pre-existing conditions such as endothelial dysfunction. The overlapping mechanisms of HIV and SARS-CoV-2, particularly the prolonged inflammatory response and chronic hypoxia, may increase susceptibility to Long COVID. Addressing these overlapping health issues is critical as it provides clinical entry points for interventions that could improve and enhance outcomes and quality of life for those affected by both HIV and Long COVID in the region.

Proteomic analysis of endothelial cells and extracellular vesicles in response to indoxyl sulfate: Mechanisms of endothelial dysfunction in chronic kidney disease

AimsCardiovascular pathology is the main cause of death in chronic kidney disease (CKD) patients. CKD is associated with the accumulation of uremic toxins in the bloodstream, and indoxyl sulfate (IS) is one of the most abundant uremic toxins found in the blood of CKD patients. We conducted an in vitro study to assess the mechanisms underlying the IS-induced endothelial dysfunction that could lead to cardiovascular diseases. We also studied their extracellular vesicles (EVs) owing to their capacity to act as messengers that transmit signals through their cargo. Main methodsEVs were characterized by nanoparticle tracking analysis, transmission electron microscopy, flow cytometry, and tetraspanin expression. Cell lysates and isolated EVs were analyzed using liquid chromatography coupled with mass spectrometry, followed by Gene Set Enrichment Analysis to identify the altered pathways. Key findingsProteomic analysis of endothelial cells revealed that IS causes an increase in proteins related to adipogenesis, inflammation, and xenobiotic metabolism and a decrease in proliferation. Extracellular matrix elements, as well as proteins associated with myogenesis, response to UV irradiation, and inflammation, were found to be downregulated in IS-treated EVs. Fatty acid metabolism was also found to be increased along with adipogenesis and inflammation observed in cells. SignificanceThe treatment of endothelial cells with IS increased the expression of proteins related to adipogenesis, inflammation, and xenobiotic metabolism and was less associated with proliferation. Furthermore, EVs from cells treated with IS may mediate endothelial dysfunction, since they present fewer extracellular matrix elements, myogenesis, inflammatory factors, and proteins downregulated in response to UV radiation.

The Impact of Endothelial Dysfunction on the Course of Metabolically Associated Liver Disease in Combination with Subclinical Hypothyroidism

Background. Intrahepatic endothelial dysfunction is involved in many diseases, including fatty liver disease, and in combination with other numerous mechanisms may play a role in atherosclerosis in hypothyroidism. It is possible that endothelial dysfunction markers may be important in assessing the risk of cardiovascular events in patients with metabolic-associated fatty liver disease (MAFLD) in combination with subclinical hypothyroidism. Aims. The aim of this study was to evaluate changes in endothelial dysfunction markers in patients with MAFLD in combination with subclinical hypothyroidism. Methods. We studied 298 patients aged 40-69 years with a history of MAFLD. Of these, 128 patients had a verified diagnosis of both MAFLD and subclinical hypothyroidism. In such cases, the morphological state of the vascular endothelium was assessed by counting circulating desquamated epithelial cells (CDEC) and vascular endothelial growth factor (VEGF-A) in the blood using phase-contrast microscopy and the value of these parameters was in comparison todepending on the level of thyroid stimulating hormone, insulin, age, and cardiovascular risk. Results. It was found that the level of CDEC and VEGF-A was increased in patients with MAFLD and subclinical hypothyroidism. On the one hand, thyroid stimulating hormone levels were found to be associated with endothelial dysfunction and hyperinsulinemia. On the other hand, endothelial dysfunction indices also have links with the degree of cardiovascular risk. Patients with moderate and high cardiovascular risk have a relationship between CDEC and levels of triglycerides, C-reactive protein, and сardiovascular diseases. The levels of VEGF-A and CDEC were significantly higher in the adult age group. VEGF-A levels > 273 pg/mL were associated with abnormalities in the studied parameters, including those reflecting of the liver. Conclusion. Patients with MAFLD in combination with hypertension have elevated levels of CDEC and VEGF-A, which affects the involvement of these factors in the mechanisms of endothelial dysfunction in this category. Markers of endothelial dysfunction can be used to assess the prediction of possible cardiometabolic risk.

Abstract P231: Lipoprotein Lipase Activation Is A Novel Anti-contractile Mechanism That Is Both Endothelium-dependent And Independent.

Risk factors such as hypertriglyceridemia and hypercholesterolemia are commonly attributed to the pathogenesis of atherosclerosis, however, lipoprotein metabolism is also associated with end organ damage and cardiovascular events in hypertensive patients. Lipoprotein lipase (LPL) is an important hydrolase for lipoprotein catabolism. Previous work from our lab has shown that LPL activator, NO-1886 (Ibrolipim), significantly decreased vascular contraction. Physiologically, endothelial function limits contractility and endothelial dysfunction is a hallmark of hypertension. Therefore, we hypothesized that LPL activation would cause endothelial-dependent hypocontractility. To test this hypothesis, mesenteric resistance arteries (MRA) were isolated from male Fischer 344 rats at 3 months of age (n=4-12) and mounted onto a wire myograph. Phenylephrine (PE) concentration-response curves were performed with and without LPL activator, NO-1886 (30 min). Some MRA were denuded of their endothelium or incubated with inhibitors of endothelium-dependent vasodilation. As expected, activating LPL exerted a significant anti-contractile effect in a concentration-dependent manner [KCl (%), Veh: 125±3 vs. NO-1886 (1 uM): 116.0±17 vs. NO-1886 (10 uM): 108±9* vs. NO-1886 (50 uM): 55±4* vs. NO-1886 (100 uM): 29±5*, *p<0.05 vs. Veh]. However, contrary to our hypothesis, denudation only partially restored contraction [KCl (%),Veh: 125±3 vs. NO-1886 (50 uM): 55±4* vs. NO-1886+denuded: 76±4* # , *p<0.05 vs. Veh, # p<0.05 vs. NO-1886]. This suggests that there is both an endothelium-dependent and -independent mechanism by which LPL limits contractility. Endothelial-dependent hypocontractility was found to be mediated by nitric oxide synthase [KCl (%),Veh: 125±3 vs. NO-1886 (50 uM): 55±4 vs. NO-1886+L-NAME (100 uM): 90±5* # , *p<0.05 vs. Veh, # p<0.05 vs. NO-1886]. Endothelium-independent mechanisms by which NO-1886 causes hypocontractility have yet been clarified (data not shown). Overall, this suggests that LPL has an important physiological role in controlling vascular contraction through both endothelial-dependent and -independent means and loss of LPL activity could be a novel mechanism of endothelial dysfunction in hypertension.

Type 1 Diabetes Impairs Endothelium-Dependent Relaxation Via Increasing Endothelial Cell Glycolysis Through Advanced Glycation End Products, PFKFB3, and Nox1-Mediated Mechanisms.

Type 1 diabetes (T1D) is a major cause of endothelial dysfunction. Although cellular bioenergetics has been identified as a new regulator of vascular function, whether glycolysis, the primary bioenergetic pathway in endothelial cells (EC), regulates vascular tone and contributes to impaired endothelium-dependent relaxation (EDR) in T1D remains unknown. Experiments were conducted in Akita mice with intact or selective deficiency in EC PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3), the main regulator of glycolysis. Seahorse analyzer and myography were employed to measure glycolysis and mitochondrial respiration, and EDR, respectively, in aortic explants. EC PFKFB3 (Ad-PFKFB3) and glycolysis (Ad-GlycoHi) were increased in situ via adenoviral transduction. T1D increased EC glycolysis and elevated EC expression of PFKFB3 and NADPH oxidase Nox1 (NADPH oxidase homolog 1). Functionally, pharmacological and genetic inhibition of PFKFB3 restored EDR in T1D, while in situ aorta EC transduction with Ad-PFKFB3 or Ad-GlycoHi reproduced the impaired EDR associated with T1D. Nox1 inhibition restored EDR in aortic rings from Akita mice, as well as in Ad-PFKFB3-transduced aorta EC and lactate-treated wild-type aortas. T1D increased the expression of the advanced glycation end product precursor methylglyoxal in the aortas. Exposure of the aortas to methylglyoxal impaired EDR, which was prevented by PFKFB3 inhibition. T1D and exposure to methylglyoxal increased EC expression of HIF1α (hypoxia-inducible factor 1α), whose inhibition blunted methylglyoxal-mediated EC PFKFB3 upregulation. EC bioenergetics, namely glycolysis, is a new regulator of vasomotion and excess glycolysis, a novel mechanism of endothelial dysfunction in T1D. We introduce excess methylglyoxal, HIF1α, and PFKFB3 as major effectors in T1D-mediated increased EC glycolysis.

Research Progress on Angiogenesis Imbalance and Pathogenesis of Preeclampsia and Predictive Treatment

Preeclampsia, one of the unique diseases of pregnancy, is a systemic vascular disease induced by various factors. Its main feature is that new-onset hypertension and proteinuria will appear after 20 weeks of pregnancy. Preeclampsia is the main cause of morbidity and mortality in pregnant women and perinatal babies. Many clinical and experimental studies have shownthat the pathological basis of preeclampsia is maternal endothelial dysfunction caused by placental factors. Moreover, it has been determined that the increase in placental anti-angiogenic factors is the main cause of vascular endothelial dysfunction and systemic vascular dysfunction in pregnant women. This review summarizes the latest advancesin the molecular mechanisms of endothelial dysfunction caused by placental anti-angiogenic factors and new clinical strategies based on these findings.

Cardiovascular risk in patients receiving antihypertensive drug treatment from the perspective of endothelial function.

Blood-pressure-lowering therapy with antihypertensive drugs can reduce the risk of cardiovascular morbidity and mortality in patients with hypertension. However, patients treated with antihypertensive drugs generally have a worse prognosis than untreated individuals. Consistent with the results obtained from epidemiological studies, a clinical study showed that endothelial function was impaired more in treated patients with hypertension than in untreated individuals with the same blood pressure level, suggesting that blood-pressure-lowering therapy with currently available antihypertensive drugs cannot restore endothelial function to the level of that in untreated individuals. Several mechanisms of endothelial dysfunction in treated patients are postulated: irreversible damage to the endothelium caused by higher cumulative elevated blood pressure exposure over time; the persistence of the primary causes of hypertension even after the initiation of antihypertensive drug treatment, including an activated renin-angiotensin-aldosterone system, oxidative stress, and inflammation; and higher global cardiovascular risk related not only to conventional cardiovascular risk factors but also to undetectable nonconventional risk factors. Lifestyle modifications/nonpharmacological interventions should be strongly recommended for both untreated and treated individuals with hypertension. Lifestyle modifications/nonpharmacological interventions may directly correct the primary causes of hypertension, which can improve endothelial function and consequently reduce cardiovascular risk regardless of the use or nonuse of antihypertensive drugs.

Extracellular vesicles from ALI models induce endothelial dysfunction

One distinguishing characteristic of acute respiratory distress syndrome (ARDS) or its lesser form, acute lung injury (ALI), is dysfunction of the lung endothelium. This dysfunction leads to increased permeability and eventual pulmonary edema. Despite the globally climbing rates of ARDS, the mechanisms of endothelial dysfunction are poorly understood. Recently, extracellular vesicles (EVs) have been shown to induce various microvascular disease states, as they contain various endothelial‐targeting cargo in the form of mRNA, proteins, lipids, and miRNAs. Therefore, we hypothesized that EVs play a role in the endothelial dysfunction observed in ARDS/ALI. EVs were isolated from the plasma of male Sprague Dawley rats which were given saline or P. aeruginosa (PA103) via intratracheal (IT) injection for 48h. ALI was confirmed by determining the wet to dry weights of the rodent lungs. We then tested the effect of the EVs isolated from saline‐ and ALI treated animals (sEVs and ALI‐EVs, respectively) on endothelial barrier function and modifications in gene expression. We found that treatment with ALI‐EVs, but not sEVs, increased rat lung microvascular endothelial cell (RLMVEC) permeability in the presence of lipopolysaccharide (LPS). Interestingly, ALI‐EVs did not induce endothelial dysfunction on their own, rather exacerbated the damage induced by LPS. We further noted ALI‐EVs, but not sEVs, increased gene expression of toll‐like receptor 4 (TLR4), which is the main pattern recognition receptor (PRR) for LPS and its downstream signaling molecule, MyD88 in the presence of LPS in RLMVEC. Further, we found that ALI‐EVs, together with LPS, increased gene expression of intracellular adhesion molecule 1 (ICAM‐1), vascular adhesion molecule 1 (VCAM‐1), and interleukin 6 (IL‐6), which are all involved in inflammatory signaling. Thus, it is likely that through the modulation of inflammatory signaling mediators, ALI‐EVs contain select cargo that worsen the endothelial barrier in settings where LPS is present, such as bacterial‐ARDS.

Integration of Metabolomics and Proteomics in Exploring the Endothelial Dysfunction Mechanism Induced by Serum Exosomes From Diabetic Retinopathy and Diabetic Nephropathy Patients.

BackgroundThe prevalence of diabetic microvascular diseases has increased significantly worldwide, the most common of which are diabetic nephropathy (DN) and diabetic retinopathy (DR). Microvascular endothelial cells are thought to be major targets of hyperglycemic damage, while the underlying mechanism of diffuse endothelial dysfunction in multiple organs needs to be further investigated.AimThe aim of this study is to explore the endothelial dysfunction mechanisms of serum exosomes (SExos) extracted from DR and DN (DRDN) patients.MethodsIn this study, human glomerular endothelial cells (HGECs) were used as the cell model. Metabolomics ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and proteomics tandem mass tag (TMT)-based liquid chromatography-tandem mass spectrometry (LC-MS/MS) together with bioinformatics, the correlation analysis, and the joint pathway analysis were employed to discover the underlying mechanisms of endothelial dysfunction caused by patient’s SExos.ResultsIt can be assumed that serum exosomes extracted by DRDN patients might cause endothelial dysfunction mainly by upregulating alpha subunit of the coagulation factor fibrinogen (FIBA) and downregulating 1-methylhistidine (1-MH). Bioinformatics analysis pointed to an important role in reducing excess cysteine and methionine metabolism.ConclusionFIBA overexpression and 1-MH loss may be linked to the pathogenicity of diabetic endothelial dysfunction in DR/DN, implying that a cohort study is needed to further investigate the role of FIBA and 1-MH in the development of DN and DR, as well as the related pathways between the two proteins.

Pulmonary Hypertension and COVID-19.

Coronavirus disease 2019 (COVID-19) is a primary respiratory infectious disease, which can result in pulmonary and cardiovascular complications. From its first appearance in the city of Wuhan (China), the infection spread worldwide, leading to its declaration as a pandemic on March 11, 2020. Clinical research on SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) suggests that the virus may determine changes in the pulmonary hemodynamics through mechanisms of endothelial dysfunction, vascular leak, thrombotic microangiopathy, and venous thromboembolism that are similar to those leading to pulmonary hypertension (PH). Current available studies report echocardiographic signs of PH in approximately 12 to 13% of hospitalized patients with COVID-19. Those with chronic pulmonary obstructive disease, congestive heart failure, pulmonary embolism, and prior PH are at increased risk to develop or worsen PH. Evidence of PH seems to be associated with increased disease severity and poor outcome. Because of the importance of the pulmonary hemodynamics in the pathophysiology of COVID-19, there is growing interest in exploring the potential therapeutical benefits of inhaled vasodilators in patients with COVID-19. Treatment with inhaled nitric oxide and prostacyclin has shown encouraging results through improvement of systemic oxygenation, reduction of systolic pulmonary arterial pressure, and prevention of right ventricular failure; however, data from randomized control trials are still required.

ENDOTHELIAL FUNCTION IN PATIENTS WITH COPD AND CARDIOVASCULAR DISEASE (REVIEW)

Cardiovascular pathology is one of the frequent comorbidities in patients with chronic obstructive pulmonary disease, due to both genetic predisposition and common risk factors (smoking, senile age, male gender, sedentary lifestyle, obesity). The article shows that development of endothelial dysfunction is one of the earliest phases of pathogenesis in this setting. Endothelial dysfunction mechanisms are defined and characterized, including an imbalance of vasoconstricting and vasodilating agents with the emergence of "vicious circles" that violate hemo-vascular homeostasis. The role of nitric oxide, endothelin-1, intercellular adhesion molecule-1 (ICAM-1) in the development of endothelial dysfunction in COPD patients is discussed. The article defines the concept of oxidative stress, the most potent oxidants and mechanisms of their damaging effect arebeing listed. A particular attention is paid to 8-isoprostane as a golden standard in assessment of oxidative stress in patients with COPD.

Endothelial dysfunction in nonalcoholic fatty liver disease

Introduction. The prevalence of nonalcoholic fatty liver disease (NAFLD) in western countries is increasing rapidly and is considered as component of metabolic syndrome. Endothelial dysfunction is a pathophysiological problem of cardiovascular disease. NAFLD, as a component of metabolic syndrome, is associated with endothelial dysfunction. 
 Material and methods. PubMed database was used in order to review and select articles according to the keywords. A total of 216 articles matching search criteria were found between 2000-2021. 
 Results. The present study has been underlined the role of pathophysiological mechanisms of endothelial dysfunction in nonalcoholic fatty liver disease, which involves oxidative stress, inflammation and insulin resistance. The main factor in the occurrence of endothelial dysfunction is related to nitric oxide (NO) biosynthesis. The markers associated with regulation of nitric oxide biosynthesis, such as asymmetric dimethylarginine, free fatty acid, lectin-like oxidized low-density lipoprotein (LDL) receptor-1 and pentraxin-3, are potential targets in the assessment of endothelial dysfunction. 
 Conclusions. Insulin resistance, inflammation and oxidative stress have been involved in the reduction of NO biosynthesis that influences the occurrence of endothelial dysfunction. Markers, such as lectin-like oxidized LDL receptor-1 and pentraxin-3, have been considered as potential targets in the assessment of endothelial dysfunctions in NAFLD.

Derivation and characterisation of endothelial cells from patients with chronic thromboembolic pulmonary hypertension

Pulmonary endarterectomy (PEA) resected material offers a unique opportunity to develop an in vitro endothelial cell model of chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to comprehensively analyze the endothelial function, molecular signature, and mitochondrial profile of CTEPH-derived endothelial cells to better understand the pathophysiological mechanisms of endothelial dysfunction behind CTEPH, and to identify potential novel targets for the prevention and treatment of the disease. Isolated cells from specimens obtained at PEA (CTEPH-EC), were characterized based on morphology, phenotype, and functional analyses (in vitro and in vivo tubule formation, proliferation, apoptosis, and migration). Mitochondrial content, morphology, and dynamics, as well as high-resolution respirometry and oxidative stress, were also studied. CTEPH-EC displayed a hyperproliferative phenotype with an increase expression of adhesion molecules and a decreased apoptosis, eNOS activity, migration capacity and reduced angiogenic capacity in vitro and in vivo compared to healthy endothelial cells. CTEPH-EC presented altered mitochondrial dynamics, increased mitochondrial respiration and an unbalanced production of reactive oxygen species and antioxidants. Our study is the foremost comprehensive investigation of CTEPH-EC. Modulation of redox, mitochondrial homeostasis and adhesion molecule overexpression arise as novel targets and biomarkers in CTEPH.

Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies.

The endothelium, a cellular monolayer lining the blood vessel wall, plays a critical role in maintaining multiorgan health and homeostasis. Endothelial functions in health include dynamic maintenance of vascular tone, angiogenesis, hemostasis, and the provision of an antioxidant, anti-inflammatory, and antithrombotic interface. Dysfunction of the vascular endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion and hyperpermeability, and endothelial cell senescence. Recent studies have implicated altered endothelial cell metabolism and endothelial-to-mesenchymal transition as new features of endothelial dysfunction. Endothelial dysfunction is regarded as a hallmark of many diverse human panvascular diseases, including atherosclerosis, hypertension, and diabetes. Endothelial dysfunction has also been implicated in severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive drugs, and antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors and interleukin 1β monoclonal antibodies, counter endothelial dysfunction as part of their clinical benefits. The regulation of endothelial dysfunction by noncoding RNAs has provided novel insights into these newly described regulators of endothelial dysfunction, thus yielding potential new therapeutic approaches. Altogether, a better understanding of the versatile (dys)functions of endothelial cells will not only deepen our comprehension of human diseases but also accelerate effective therapeutic drug discovery. In this review, we provide a timely overview of the multiple layers of endothelial function, describe the consequences and mechanisms of endothelial dysfunction, and identify pathways to effective targeted therapies. SIGNIFICANCE STATEMENT: The endothelium was initially considered to be a semipermeable biomechanical barrier and gatekeeper of vascular health. In recent decades, a deepened understanding of the biological functions of the endothelium has led to its recognition as a ubiquitous tissue regulating vascular tone, cell behavior, innate immunity, cell-cell interactions, and cell metabolism in the vessel wall. Endothelial dysfunction is the hallmark of cardiovascular, metabolic, and emerging infectious diseases. Pharmacotherapies targeting endothelial dysfunction have potential for treatment of cardiovascular and many other diseases.

Coronary microvascular adaptations distal to epicardial artery stenosis.

Until recently, epicardial coronary stenosis has been considered the primary outcome of coronary heart disease, and clinical interventions have been dedicated primarily to the identification and removal of flow-limiting stenoses. However, a growing body of literature indicates that both epicardial stenosis and microvascular dysfunction contribute to damaging myocardial ischemia. In this review, we discuss the coexistence of macro- and microvascular disease, and how the structure and function of the distal microcirculation is impacted by the hemodynamic consequences of an epicardial, flow-limiting stenosis. Mechanisms of endothelial dysfunction as well as alterations of smooth muscle function in the coronary microcirculation distal to stenosis are discussed. Risk factors including diabetes, metabolic syndrome, and aging exacerbate microvascular dysfunction in the myocardium distal to a stenosis, and our current understanding of the role of these factors in limiting collateralization and angiogenesis of the ischemic myocardium is presented. Importantly, exercise training has been shown to promote collateral growth and improve microvascular function distal to stenosis; thus, the current literature reporting the mechanisms that underlie the beneficial effects of exercise training in the microcirculation distal to epicardial stenosis is reviewed. We also discuss recent studies of therapeutic interventions designed to improve microvascular function and stimulate angiogenesis in clinically relevant animal models of epicardial stenosis and microvascular disease. Finally, microvascular adaptation to removal of epicardial stenosis is considered.

Fatal Mesenteric Ischemia in a Severely Ill COVID-19 Patient: a Case Report

Background: Emerging data suggest a complex role for immuno-thrombosis in the thrombotic complications in COVID-19. We report the case of a fatal mesenteric ischemia to illustrate the mechanisms of endothelial dysfunction in the gut, and the resulting hypercoagulability. Case Report: A 58-year-old woman was admitted in Intensive Care Unit, with initial severe acute respiratory distress syndrome due to SARS-CoV-2 pneumonia. Her respiratory status worsened, with a septic shock thirteen days after symptoms onset. The blood culture was positive with Pseudomonas aeruginosa and Candida. A rapid consecutive deterioration leading to multiorgan failure revealed colic perforation complicated with secondary peritonitis. Histopathological findings revealed small vein occlusions. Surprisingly, no SARS-CoV-2 viral particles could be detected in the bowel. We found intense endothelial dysfunction, contrasting with only mild neutrophil activation. A major increase in von Willebrand factor and resistance to fibrinolysis were the main hemostatic abnormalities. Discussion: This case highlights that COVID-19-associated hypercoagulability can lead to early primitive thrombotic events in small vessels, and adds new evidence concerning a potential role for immuno-thrombosis. Close monitoring of endothelial dysfunction, and further consideration of new targets to prevent thrombosis by adjunctive therapies may thus appear fundamental.

Features of the Functional State of the L-arginine / NO-synthase / Arginase System and Oxidative Processes in Patients with end-stage Renal Disease due to Chronic Glomerulonephritis Before and After a Hemodialysis Session

Features of the Functional State of the L-arginine / NO-synthase / Arginase System and Oxidative Processes in Patients with end-stage Renal Disease due to Chronic Glomerulonephritis Before and After a Hemodialysis Session

Molecular and genetic mechanisms of endothelial dysfunction in children with allergic enteropathy

Objective. The objective is to analyze molecular and genetic mechanisms of endothelial dysfunction development in children with allergic enteropathy.Methods: We have studied the polymorphisms of endothelial nitric oxide synthase gene and the level of nitric oxide metabolites in coprofiltrates in 43 children aged from 6 months to 3 years with allergic enteropathy.Results: The endothelial dysfunction in allergic enteropathy is associated with nitric oxide molecule. Carriage of the homozygous allele СС Т786С of the endothelial nitric oxide synthase gene raises the risk of IgE-independent food allergy development by 8.8 times.Conclusions: The conducted study evidences the active participation of nitric-oxidergic mechanism in allergic inflammation development.

ENDOTHELIAL DYSFUNCTION IN TYPE 2 DIABETES. Review

Relevance. The problem of systematization and refinement of modern concepts of the pathogenesis of endothelial dysfunction (EDF) and its role in the development of microvascular complications of type 2 diabetes mellitus (T2DM) is relevant due to the lack of pathogenetic treatment nowadays, which would include endothelial dysfunction.
 Objective: to conduct an analytical review of the results of scientific research on the mechanisms of EDF in T2DM, with the aim of proposing an integrated modern concept of the pathogenesis of EDF.
 Materials and methods. Review of scientific publications in the international electronic scientific databases of PubMed, Embase and Scopus for keywords for the entire available period (1982-2019).
 Results. The article provides modern data on the modern concept of the pathogenesis of EDF and its role in the development of microvascular complications in T2DM. The pathogenesis of EDF in type 2 diabetes mellitus is based on the following key mechanisms: impaired synthesis of the endothelial fraction of nitric oxide (NO) due to inhibition of the activity of endothelial NO synthase (eNOS); decreased bioavailability of NO because of oxidative stress; activation of the formation of Endothelin-1 (ET1) and expression of endothelin receptors with a predominance of vasoconstriction; inflammation, which is supported by the synthesis of pro-inflammatory cytokines and causes the expression of inducible NO synthase (iNOS), which stimulates the synthesis of a significant amount of NO, which enters into free radical reactions with the formation of cytotoxic products.
 Conclusions. The pathogenesis of endothelial dysfunction is impaired nitric oxide synthesis. Endothelial dysfunction, as an integral mechanism, underlies in the core mechanisms the development of vascular complications in type 2 diabetes.