Mechanisms Of Endothelial Injury Research Articles

Bioinformatics-based analysis of mechanistic differences in vascular endothelial injury ischemic stroke induced by atrial fibrillation and atherosclerosis.

Studies of the intracranial vasculature in patients with ischemic stroke caused by atherosclerosis (AS) and cardiac embolism have revealed significantly different degrees of AS, plaque, and vascular stenosis. And the endothelium has a great influence on the vasculature throughout the circulatory system, especially in the brain. This study aimed to investigate the mechanistic differences in endothelial injury between atrial fibrillation (AF)- and AS-induced ischemic stroke. All target genes of AF, AS, and the vascular endothelial cell (VC) were obtained from the GeneCards database; the differential genes of AF and AS separately associated with the VC were established by a Venn diagram. A protein-protein interaction network was created, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were used to perform genomic enrichment and functional enrichment analysis. Hub genes were selected by Maximal Clique Centrality algorithm ranking and correlation linkage in the STRING database, and then, clinical serum samples were used to verify the quantitative expressions in the AF, AF stroke, AS, and AS stroke groups. Fifty-five AF-VC-related genes and ninety-three AS-VC-related genes were screened, which differed in biological function, cellular composition, and molecular function. The genes correlation between AF and vascular endothelial cells (VCs) was KRAS and PTPN11, and those correlation between AS and VCs was IL-4, IFNG, IL-17A, and CSF-2. IL-4 and CSF-2 may be relevant proteins involved in the differences in stroke mechanisms between AF and AS, and they may act by further influencing the function of their downstream cells. This study provides a preliminary theoretical basis for investigating the differences in mechanisms of endothelial injury between AF- and AS-induced ischemic stroke.

Research progress in endothelial cell injury and repair.

Endothelial cells, which are important metabolic and endocrine cells, play an important role in regulating vascular function. The occurrence and development of various cardiovascular and cerebrovascular diseases are associated with endothelial dysfunction. However, the underlying mechanism of vascular endothelial injury is not fully understood. It has been reported that the mechanism of endothelial injury mainly involves inflammation and oxidative stress. Moreover, endothelial progenitor cells are regarded as important contributors in repairing damaged endothelium. Multiple interventions (including chemical drugs and traditional Chinese medicines) exert endothelial protection by decreasing the release of inducing factors, suppressing inflammation and oxidative stress, and preventing endothelial cell senescence.

Normal Saline solutions cause endothelial dysfunction through loss of membrane integrity, ATP release, and inflammatory responses mediated by P2X7R/p38 MAPK/MK2 signaling pathways.

Resuscitation with 0.9% Normal Saline (NS), a non-buffered acidic solution, leads to increased morbidity and mortality in the critically ill. The goal of this study was to determine the molecular mechanisms of endothelial injury after exposure to NS. The hypothesis of this investigation is that exposure of endothelium to NS would lead to loss of cell membrane integrity, resulting in release of ATP, activation of the purinergic receptor (P2X7R), and subsequent activation of stress activated signaling pathways and inflammation. Human saphenous vein endothelial cells (HSVEC) incubated in NS, but not buffered electrolyte solution (Plasma-Lyte, PL), exhibited abnormal morphology and increased release of lactate dehydrogenase (LDH), adenosine triphosphate (ATP), and decreased transendothelial resistance (TEER), suggesting loss of membrane integrity. Incubation of intact rat aorta (RA) or human saphenous vein in NS but not PL led to impaired endothelial-dependent relaxation which was ameliorated by apyrase (hydrolyzes ATP) or SB203580 (p38 MAPK inhibitor). Exposure of HSVEC to NS but not PL led to activation of p38 MAPK and its downstream substrate, MAPKAP kinase 2 (MK2). Treatment of HSVEC with exogenous ATP led to interleukin 1β (IL-1β) release and increased vascular cell adhesion molecule (VCAM) expression. Treatment of RA with IL-1β led to impaired endothelial relaxation. IL-1β treatment of HSVEC led to increases in p38 MAPK and MK2 phosphorylation, and increased levels of arginase II. Incubation of porcine saphenous vein (PSV) in PL with pH adjusted to 6.0 or less also led to impaired endothelial function, suggesting that the acidic nature of NS is what contributes to endothelial dysfunction. Volume overload resuscitation in a porcine model after hemorrhage with NS, but not PL, led to acidosis and impaired endothelial function. These data suggest that endothelial dysfunction caused by exposure to acidic, non-buffered NS is associated with loss of membrane integrity, release of ATP, and is modulated by P2X7R-mediated inflammatory responses.

Chapter 26 - Posterior reversible encephalopathy in the intensive care unit

Posterior reversible encephalopathy syndrome (PRES) is increasingly diagnosed in the emergency department, and medical and surgical intensive care units. PRES is characterized by acute onset of neurologic symptoms in the setting of blood pressure fluctuations, eclampsia, autoimmune disease, transplantation, renal failure, or exposure to immunosuppressive or cytotoxic drugs, triggers known to admit patients to the intensive care unit (ICU). Although the exact pathophysiology remains unknown, there is growing consensus that PRES results from endothelial dysfunction. Because of the heterogeneous nature of the disorder, it is probable that different mechanisms of endothelial injury are etiologically important in different clinical situations. The presence of bilateral vasogenic edema on brain imaging, particularly in parieto-occipital regions, is of great diagnostic utility but PRES remains a clinical diagnosis. Although largely reversible, PRES can result in irreversible neurologic injury and even death. The range of clinical and radiographic manifestations of the syndrome is probably broader than previously thought, and it is imperative that clinicians become familiar with the full spectrum of the disorder, as prompt recognition and elimination of an inciting factor improve outcome. PRES may be the most frequent toxic-metabolic encephalopathy seen in the ICU.

Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy

AbstractHematopoietic stem cell transplant (HSCT)-associated thrombotic microangiopathy (TMA) is a complication that occurs in 25% to 35% of HSCT recipients and shares histomorphologic similarities with hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). The hallmark of all thrombotic microangiopathies is vascular endothelial cell injury of various origins, resulting in microangiopathic hemolytic anemia, platelet consumption, fibrin deposition in the microcirculation, and tissue damage. Although significant advances have been made in understanding the pathogenesis of other thrombotic microangiopathies, post-HSCT TMA remains poorly understood. We report an analysis of the complement alternative pathway, which has recently been linked to the pathogenesis of both the Shiga toxin mediated and the atypical forms of HUS, with a focus on genetic variations in the complement Factor H (CFH) gene cluster and CFH autoantibodies in six children with post-HSCT TMA. We identified a high prevalence of deletions in CFH-related genes 3 and 1 (delCFHR3-CFHR1) and CFH autoantibodies in these patients with HSCT-TMA. Conversely, CFH autoantibodies were not detected in 18 children undergoing HSCT who did not develop TMA. Our observations suggest that complement alternative pathway dysregulation may be involved in the pathogenesis of post-HSCT TMA. These findings shed light on a novel mechanism of endothelial injury in transplant-TMA and may therefore guide the development of targeted treatment interventions.

Endothelial cell injury by high glucose and heparanase is prevented by insulin, heparin and basic fibroblast growth factor

BackgroundUncontrolled hyperglycemia is the main risk factor in the development of diabetic vascular complications. The endothelial cells are the first cells targeted by hyperglycemia. The mechanism of endothelial injury by high glucose is still poorly understood. Heparanase production, induced by hyperglycemia, and subsequent degradation of heparan sulfate may contribute to endothelial injury. Little is known about endothelial injury by heparanase and possible means of preventing this injury.ObjectivesTo determine if high glucose as well as heparanase cause endothelial cell injury and if insulin, heparin and bFGF protect cells from this injury.MethodsCultured porcine aortic endothelial cells were treated with high glucose (30 mM) and/or insulin (1 U/ml) and/or heparin (0.5 μg/ml) and /or basic fibroblast growth factor (bFGF) (1 ng/ml) for seven days. Cells were also treated with heparinase I (0.3 U/ml, the in vitro surrogate heparanase), plus insulin, heparin and bFGF for two days in serum free medium. Endothelial cell injury was evaluated by determining the number of live cells per culture and lactate dehydrogenase (LDH) release into medium expressed as percentage of control.ResultsA significant decrease in live cell number and increase in LDH release was found in endothelial cells treated with high glucose or heparinase I. Insulin and/or heparin and/or bFGF prevented these changes and thus protected cells from injury by high glucose or heparinase I. The protective ability of heparin and bFGF alone or in combination was more evident in cells damaged with heparinase I than high glucose.ConclusionEndothelial cells injured by high glucose or heparinase I are protected by a combination of insulin, heparin and bFGF, although protection by heparin and/or bFGF was variable.

Endothelin in the mechanism of endothelial injury and neutrophil adhesion in the post-ischemic guinea-pig heart

This study addressed the hypothesis that endothelin promotes neutrophil accumulation in ischemic/reperfused myocardium, not only via its direct effect on neutrophils, but also because it mediates post-ischemic endothelial injury. Langendorff-perfused guinea-pig hearts were subjected to 30 min ischemia/35 min reperfusion, and infusion of neutrophils between 15 and 25 min of reperfusion. The infusion of the endothelin ET A/ET B receptor antagonist, tezosentan, the endothelin ET A receptor antagonist, BQ 123 [cyclo(- d-Trp- d-Asp-Pro- d-Val-Leu-], and superoxide dismutase was terminated at reperfusion, 5 min before the start of the neutrophil infusion, to avoid the contact of the drugs with neutrophils. Coronary flow responses to acetylcholine and nitroprusside were used as measures of endothelium-dependent and -independent vascular function, respectively. Neutrophil adhesion and endothelium glycocalyx ultrastructure were assessed in histological preparations. Ischemia/reperfusion resulted in a 54%-impaired acetylcholine response, endothelium glycocalyx disruption, and enhanced neutrophil adhesion (21.6% of microvessels contained neutrophils vs. 2.6% in sham group), the latter prevented by a selectin blocker, sulfatide, 20 μg/ml. These alterations were completely prevented by 0.5 and 5 nM, but not 0.05 nM, tezosentan, and were greatly attenuated by BQ 123, 1 and 10 nM. The glycocalyx-protective effect of these interventions preceded their effect on neutrophil adhesion. Superoxide dismutase, 150 IU/ml, reported before by us to protect post-ischemic endothelium glycocalyx, here prevented the post-ischemic endothelial dysfunction and neutrophil adhesion. The data imply that neutrophil adhesion in ischemic/reperfused guinea-pig heart is a selectin-dependent process, secondary to mostly endothelin ET A receptor- and free radical-mediated functional and/or structural changes in the coronary endothelium. Thus, endothelin ET A/ET B as well as ET A receptor antagonists may be useful in attenuation of the inflammatory response in ischemic/reperfused heart. The antagonists may be effective because of their direct effect on neutrophils, as demonstrated by others, and because they provide endothelial protection, as demonstrated here.

ACE-gene polymorphism is associated with the development of allograft vascular disease in heart transplant recipients

Background: Cardiac allograft vascular disease is (CAVD) the most important cause of death following heart transplantation (HTX). Although in the past, researchers focused predominantly on mechanisms of endothelial injury, the possible role of recipient-related and genetically determined factors has not been studied in detail. Methods Stimulated by recent observations in native coronary artery disease, we analyzed the potential impact of angiostensin-converting enzyme (ACE) polymorphism (insertion/deletion [I/D], intron 16) on development and progression of CAVD. We characterized genotype in 146 patients 1 to 12 years after HTX (121 men; mean age, 46.2 ± 11.3 years; observation period, 6.1 ± 3.8 years) and correlated genotype to the onset and progression of CAVD, defined as luminal obstruction > 50%. Results We found allelic frequencies to be 28.8% ( n = 42) for ACE-DD, 49.3% ( n = 72) for ACE-DI, and 21.9% ( n = 32) for ACE-II. Differences in actuarial freedom from vasculopathy were significant 6 years after transplantation, with 84.6% for ACE-II compared with 54.4% for ACE-DD. We observed intermediate results for ACE-DI genotype (77.3%, p = 0.015). Conclusions In this large cohort study, we demonstrated a close relationship between the recipient-related ACE-D genotype and development of advanced CAVD. These observations suggest that gene–environment interactions might be clinically important in coronary vasculopathy after HTX.

Potential role of an endothelium-specific growth factor, hepatocyte growth factor, on endothelial damage in diabetes.

Endothelial cells are known to secrete various antiproliferative and vasodilating factors. Although injury of endothelial cells has been postulated as an initial trigger of the progression of atherosclerosis in patients with diabetes, the mechanisms of endothelial injury in diabetes are not yet clarified. Therefore, it is important to know the effects of high glucose on the factors that may influence endothelial cell growth. A novel member of endothelium-specific growth factors, hepatocyte growth factor (HGF), is produced in vascular cells. To investigate the effects of high glucose on vascular cells, we examined 1) the effects of high glucose on endothelial cell and vascular smooth muscle cell (VSMC) growth and 2) the effects of high glucose on local HGF production in endothelial cell and VSMC. Treatment of human aortic endothelial cell with a high concentration of D-glucose, but not mannitol and L-glucose, resulted in a significant decrease in cell number. Interestingly, addition of recombinant HGF attenuated high D-glucose-induced endothelial cell death. Therefore, we measured local HGF secretion of endothelial cell. Importantly, local HGF production was significantly decreased by high D-glucose treatment. In contrast, high D-glucose treatment resulted in a significant increase in the number of human aortic VSMCs, whereas local HGF production was significantly decreased in accordance with increase in D-glucose concentration. No significant changes in numbers were observed in VSMC treated with high mannitol and L-glucose. We also studied the mechanisms of local HGF suppression by high D-glucose. High D-glucose treatment stimulated transforming growth factor-beta (TGF-beta) concentration in endothelial cell and VSMC. Decreased local vascular HGF production was abolished by addition of anti-TGF-beta antibody. As TGF-beta inhibited local HGF production in endothelial cell and VSMC, increased TGF-beta induced by high D-glucose may suppress local HGF production. This study demonstrated that high D-glucose induced endothelial cell death, stimulated VSMC growth, and decreased local HGF production through the stimulation of TGF-beta production both in endothelial cell and VSMC. Overall, decrease in a local endothelial stimulant, HGF, by high D-glucose may be a trigger of endothelial injury in diabetes, potentially resulting in the progression of atherosclerosis.

Overview of vasculitis: classification and pathogenesis

The aetiology of the primary systemic vasculitides remains obscure. Recent years have seen significant advances in our understanding of relevant mechanisms of inflammation and in particular the role of, and interactions between, the vascular endothelium, inflammatory mediators and immune effector cells. This has helped to elucidate further those specific processes relevant to vasculitis which result in endothelial cell damage. In Wegener's granulomatosis and microscopic polyarteritis the evidence favours an autoimmune inflammatory response, characterized by specific mediators in which the endothelium is both target and active participant. The focal nature of the lesions seen in systemic vasculitis as evident in the kidney is unlike that of other immune-mediated renal diseases and has yet to be explained. Similarly, in the absence of immune complex deposition, the mechanism of endothelial injury and the contribution to the injury by humoral and cell-mediated mechanisms need to be studied further. Other potential mechanisms of injury need to be explored. Increased understanding of the pathogenesis of systemic vasculitis is likely to provide the basis for the use of more selective immunomodulatory therapies in the future.

Vessel Wall Injury and Arterial Thrombosis Induced by a Photochemical Reaction

Arterial thrombosis may be initiated in an experimental animal by a photochemical reaction between transmural green light and i.v. administered Rose Bengal, a photosensitizer dye. In this study, scanning electron microscopy has been used to reveal the nature of vessel injury and the cellular composition of the photochemically induced thrombus. A 5 mm segment of the guinea pig femoral artery was occluded by a thrombus about 10 min after irradiation with green light in the presence of systemically administered Rose Bengal. Electron microscopy revealed that following photochemical reaction, endothelial cells first contract and, with further irradiation, become detached from the vessel wall, with their cell membrane being destroyed at the irradiated site where an occlusive platelet-rich thrombus was formed. Endothelial cell injury and vessel occlusion could be completely inhibited by the aminothiol, DL-cysteine administered i.v. 1 min after Rose Bengal. The mechanism of endothelial injury in this model appears to be by singlet molecular oxygen, 1O2 formed by energy transfer from the photo-excited dye to O2.

血小板と動脈硬化のInitiation

There are many theories concerned with the pathogenesis of atherosclerosis. The Response-to-Injury Hypothesis is one of them. We have also considered that the endothelial damage with or without thrombi plays an important role in the initiation of atherosclerosis. There have been reported many factors which injure the intima morphologically or functionally. Platelets or aggregated platelets are also considered to be one of the factors. Arachidonic acid production is considered to be an important factor in the mechanism of endothelial injury, because of its detergent action and the strong vasoconstrictive function of its further metabolized material, thromboxane A2 or entoperoxides. We attempted to clarify the direct effect of arachidonic acid on the endothelium.In the experiment I, the arachidonic acid was injected into the aorta via the tubing inserted via the left femoral artery by one shot (1mg/kg) or by snatches (four times, 0.5mg/kg each). Twenty minutes after the injection, the rabbits were sacrificed and the right femoral arteries were fixed by perfusion fixation. The dissected femoral arteries were examined by scanning and transmission electron microscope. In the experiment II, the endothelium of the thoracic and upper part of abdominal aorta was denuded by Fogarty balloon catheter inserted via the left femoral artery, and the abdominal aorta and right femoral artery were examined by scanning electron microscope.In the experiment I, the rabbits in which the arachidonic acid was injected by one shot showed no appreciable pathological change in the endothelium of the right femoral arteries besides vacuolar formation in the cytoplasm in part. The rabbits in which the arachidonic acid was injected by snatches showed various degrees of damage, shrinkage, elevation and/or vacuolation of the cytoplasm, rupture of the cytoplasmic membrane, and denudation of the endothelium only in part without platelet adhesion. In the experiment II, area of the endothelial denudation by catheter showed diffuse platelet adhesion, but no endothelial damage was observed in the right femoral artery.From these experiment, intimal changes produced by aggregated platelets or other stimuli even if the drastic amount of arachidonic acid was administered by one shot was considered to be a minute one. Dysfunction of endothelial cells and the morphological damage initiating atherosclerosis are considered to be produced by repetition of minute stimuli in vivo.