OBJECTIVES: To investigate the role and mechanism of copper overload-mediated endoplasmic reticulum stress (ERS) in vascular endothelial injury in Kawasaki disease (KD). METHODS: Four-week-old male C57BL/6 mice were randomly divided into four groups: control, KD, KD plus copper chelator tetrathiomolybdate (TTM), and KD plus ERS inhibitor AMG PERK 44 (AMG) (n=20 per group). A KD mouse model was established using Candida albicans extract. Human umbilical vein endothelial cells (HUVECs) were divided into control (intervention with healthy children's serum), KD (intervention with KD patients' serum), and KD+TTM (intervention with KD patients' serum plus 20 µmol/L TTM). Copper deposition in mouse heart tissue was assessed using rubeanic acid staining. Vascular pathological changes were observed using hematoxylin-eosin staining and measurement of abdominal aortic diameter and area. ERS activation was detected by transmission electron microscopy and immunofluorescence. HUVEC viability, apoptosis, and functional changes were evaluated using CCK8, flow cytometry, cell scratch assay, and angiogenesis experiments. ERS marker protein expression levels were measured by Western blot. RESULTS: Compared to the KD group, the KD+TTM and KD+AMG groups showed reduced copper deposition in the vascular wall, decreased swelling of coronary endothelial cells and endoplasmic reticulum, reduced inflammatory cell infiltration, and less abdominal aortic lesion expansion. The abdominal aortic diameter and area, and the fluorescence intensity of ERS marker proteins (GRP78 and CHOP) were significantly lower (P<0.05). Compared to the KD group, the KD+TTM group exhibited increased cell viability, tube number, and scratch healing rate, along with decreased apoptosis rate and expression of ERS marker proteins (GRP78, CHOP, ATF6, and p-PERK) (P<0.05). CONCLUSIONS Copper overload aggravates vascular endothelial injury in KD by activating the ERS pathway. TTM can exert protective effects on the endothelium by regulating copper metabolism and inhibiting the ERS pathway.
Endoplasmic Reticulum Stress ; Copper/toxicity* ; Male ; Mucocutaneous Lymph Node Syndrome/metabolism* ; Animals ; Humans ; Endoplasmic Reticulum Chaperone BiP ; Mice, Inbred C57BL ; Mice ; Human Umbilical Vein Endothelial Cells ; Apoptosis ; Endothelium, Vascular/injuries*

OBJECTIVE: To explore the main components and potential mechanisms of Sangqi Qingxuan Liquid in the treatment of arterial vascular endothelial cells (AVECs) injury in hypertension through network pharmacology. METHODS: Traditional Chinese Medicine Systems Pharmacology and Analysis Platform (TCMSP) and Traditional Chinese Medicine Integrated Database (TCMID) were used to screen the active components of Sangqi Qingxuan Liquid (SQQX), which met the oral utilization rate and drug similarity criteria. An active component-target network was constructed using Cytoscape 3.6 software. A protein-protein interaction (PPI) network of targets associated with SQQX treatment for hypertension was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The Metascape database was used to perform enrichment analysis of gene ontology biological functions and MSigDB pathway enrichment analysis of proteins in the PPI network. Further analysis of the main components of SQQX was performed using UPLC-MS. Based on the results of network pharmacology, the mechanism of SQQX to improve the injury of AVECs in hypertension was verified through lentiviral transfection by Wnt/ β -catenin signaling pathway. AVECs induced by angiotensin II (Ang II ) was used to establish a model of endothelial function injury in hypertension. Cell viability, intracellular nitric oxide content, malonaldehyde content, and superoxide dismutase activity were measured to determine the optimal induction conditions. The optimal intervention conditions for SQQX were determined based on cell viability, cellular DNA activity, and the gradient method. The cells were further divided into blank, model, overexpression lentivirus negative control, overexpression lentivirus, overexpression lentivirus + SQQX intervention (2.47 mg/mL, 12 h), inhibition lentivirus negative control, inhibition lentivirus, and inhibition lentivirus + SQQX intervention (2.47 mg/mL, 12 h) groups. Finally, quantitative real-time PCR and Western blotting were performed to analyze the molecular mechanisms of SQQX in the Wnt/ β -catenin signaling pathway. RESULTS: The main SQQX components were betaine, buddleoside, and chlorogenic acid, in descending order. Network pharmacology analysis screened 12 pathways associated with the hypertensive vascular endothelium. The results showed that 1 µ mol/L for 12 h was the optimal condition for Ang II to induce AVECs injury, and 2.47 mg/mL SQQX intervention for 12 h was the optimal condition for treating AVECs injury. In the experimental validation based on the interaction network of the Wnt/ β -catenin signaling pathway, SQQX significantly decreased the expressions of β -catenin, Smad2, peroxisome proliferator-activated receptors (PPARs), endothelial nitric oxide synthase (eNOS), and endothelin-1 (ET-1) caused by the β -catenin overexpression lentivirus (P<0.05 or P<0.01). The function of vascular endothelial cells can be improved by the β -catenin inhibition lentivirus, and no obvious changes were observed after further intervention with SQQX. CONCLUSION SQQX may protect against AVECs injury by regulating the Wnt/β -catenin signaling pathway.
Drugs, Chinese Herbal/therapeutic use* ; beta Catenin/metabolism* ; Hypertension/metabolism* ; Endothelial Cells/metabolism* ; Protein Interaction Maps/drug effects* ; Humans ; Wnt Signaling Pathway/drug effects* ; Network Pharmacology ; Endothelium, Vascular/injuries* ; Cell Survival/drug effects* ; Angiotensin II/pharmacology* ; Nitric Oxide/metabolism*

ObjectiveEndothelial cells (ECs) are important metabolic and endocrinal organs which play a significant role in regulating vascular function. Vascular ECs, located between the blood and vascular tissues, can not only complete the metabolism of blood and interstitial fluid but also synthesize and secrete a variety of biologically active substances to maintain vascular tension and keep a normal flow of blood and long-term patency. Therefore, this article presents a systematic review of common injuries and healing mechanisms for the vascular endothelium.

Data SourcesAn extensive search in the PubMed database was undertaken, focusing on research published after 2003 with keywords including endothelium, vascular, wounds and injuries, and wound healing.

Study SelectionSeveral types of articles, including original studies and literature reviews, were identified and reviewed to summarize common injury and repair processes of the endothelial lining.

ResultsEndothelial injury is closely related to the development of multiple cardiovascular and cerebrovascular diseases. However, the mechanism of vascular endothelial injury is not fully understood. Numerous studies have shown that the mechanisms of EC injury mainly involve inflammatory reactions, physical stimulation, chemical poisons, concurrency of related diseases, and molecular changes. Endothelial progenitor cells play an important role during the process of endothelial repair after such injuries. What's more, a variety of restorative cells, changes in cytokines and molecules, chemical drugs, certain RNAs, regulation of blood pressure, and physical fitness training protect the endothelial lining by reducing the inducing factors, inhibiting inflammation and oxidative stress reactions, and delaying endothelial caducity.

ConclusionsECs are always in the process of being damaged. Several therapeutic targets and drugs were seeked to protect the endothelium and promote repair.

Biological Transport ; Endothelial Cells ; Endothelium, Vascular ; injuries ; Humans ; Inflammation ; therapy

In recent years, injuries induced by explosive blast have got more and more attention owing to weapon development and frequent terrorist activities. Tear, bleeding and edema of tissues and organs are the main manifestations of blast shock wave damage. Vascular endothelial barrier is the main defense of tissues and organs' integrity. This article aims to discuss possible mechanisms of endothelial barrier damage induced by explosive blast and main manifestations of blood brain barrier, bloodeair barrier, and intestinal vascular barrier impairments. In addition, the main regulatory factors of vascular permeability are also summarized so as to provide theoretical basis for prevention and cure of vascular endothelial barrier damage resulting from explosive blast.
Blast Injuries ; metabolism ; Blood-Brain Barrier ; Capillary Permeability ; Endothelium, Vascular ; metabolism ; Humans ; Nitric Oxide ; physiology ; Platelet Activating Factor ; physiology ; Serotonin ; physiology ; Thrombin ; physiology

OBJECTIVEThis study was aimed to investigate the effects of carbon monoxide releasing molecule (CORM-2), a novel carbon monoxide carrier, on the reendothelialization of carotid artery in rat endothelial denudation model.

METHODSMale rats subjected to carotid artery balloon injury were treated with CORM-2, inactive CORM-2 (iCORM-2) or dimethyl sulfoxide (DMSO). The reendothelialization capacity was evaluated by Evans Blue dye and the immunostaining with anti-CD31 antibody. The number of circulating endothelial progenitor cells (EPCs) was detected by flow cytometry. The proliferation, migration, and adhesion of human umbilical vein endothelial cells (HUVECs) were assessed by using [3H]thymidine, Boyden chamber and human fibronectin respectively. The expressions of protein were detected by using western blot analysis.

RESULTSCORM-2 remarkably accelerated the re-endothelialization 5 d later and inhibited neointima formation 28 d later. In addition, the number of peripheral EPCs significantly increased in CORM-2-treated rats than that in iCORM-2 or DMSO-treated rats after 5 d later. In vitro experiments, CORM-2 significantly enhanced the proliferation, migration and adhesion of HUVECs. The levels of Akt, eNOS phosphorylation, and NO generation in HUVECs were also much higher in CORM-2 treated group. Blocking of PI3K/Akt/eNOS signaling pathway markedly suppressed the enhanced migration and adhesion of HUVECs induced by CORM-2.

CONCLUSIONCORM-2 could promote endothelial repair, and inhibit neointima formation after carotid artery balloon injury, which might be associated with the function changes of HUVECs regulated by PI3K/Akt/eNOS pathway.

Animals ; Carbon Monoxide ; metabolism ; pharmacology ; Carotid Artery Injuries ; drug therapy ; immunology ; metabolism ; pathology ; Carotid Artery, Common ; drug effects ; immunology ; metabolism ; pathology ; Cell Adhesion ; drug effects ; Disease Models, Animal ; Endothelial Cells ; drug effects ; immunology ; metabolism ; pathology ; Endothelium, Vascular ; drug effects ; metabolism ; pathology ; Humans ; Male ; Rats ; Rats, Sprague-Dawley

Vascular endothelium plays an important role in regulating vascular homeostasis. Over the past years, it has become clear that endothelial dysfunction is a key event of pathophysiological changes in the initiation and progression of injuries induced by extreme environmental factors. The present review summarizes current understanding of vascular endothelial dysfunction induced by hypoxia, cold and heat, and provides the information for prevention and treatment of environmental exposure injuries.
Endothelium, Vascular ; physiopathology ; Environment ; Humans ; Hypoxia ; physiopathology ; Temperature ; Vascular System Injuries

The incidence of erectile dysfunction (ED) increases with age and cardiovascular disease risk factors, such as hypertension, hyperlipidemia, insulin resistance, obesity, and diabetes. These risk factors are thought to contribute to endothelial dysfunction and atherosclerosis, thus contributing to the pathophysiology of ED. The role of the endothelium in regulating erectile physiology is well established. However, the role of androgens in modulating endothelial function and endothelial repair mechanisms subsequent to vascular injury in erectile tissue remains a subject of intensive research. The clinical and preclinical evidence discussed in this review suggests that androgens regulate endothelial function and also play an important role in the development and maturation of endothelial progenitor cells (EPCs), which are thought to play a critical role in repair of endothelial injury in vascular beds. In this review, we discuss the data available on the effects of androgens on endothelial function and EPCs in the repair of vascular injury. Indeed, more research is needed to fully understand the molecular and cellular basis of androgen action in regulating the development, differentiation, maturation, migration, and homing of EPCs to the site of injury. A better understanding of these processes will be critical to the development of new therapeutic approaches to the treatment of vascular ED.
Androgens* ; Atherosclerosis ; Cardiovascular Diseases ; Endothelial Cells ; Endothelium ; Erectile Dysfunction ; Hyperlipidemias ; Hypertension ; Incidence ; Insulin Resistance ; Male ; Nitric Oxide ; Obesity ; Risk Factors ; Stem Cells* ; Testosterone ; Vascular System Injuries

Cells, Cultured ; Curcumin ; pharmacology ; Endothelium, Vascular ; drug effects ; pathology ; radiation effects ; Human Umbilical Vein Endothelial Cells ; drug effects ; radiation effects ; Humans ; Radiation Injuries ; Signal Transduction ; drug effects ; radiation effects

OBJECTIVE: To observe the effect of soft tissue crush injury on the tensions of thoracic aortic rings (TARs) in rats and to investigate the potential roles of nitric oxide in the change of the tensions. METHODS: Thirty adult SD rats were randomly divided into control group and crush injury (8 h and 16 h after injury) groups. Two kinds of TARs (one with endothelium and the other without endothelium) in vitro were prepared. In the TARs with endothelium, the tensions induced by phenylephrine (PE), acetylcholine (Ach), calcium ionophore A23187 and angiotensin II (AngI) were measured by the vascular tension detective technique. Then the TARs with endothelium were preincubated with nitric oxide synthase inhibitor N-nitro-L-arginine (L-NNA) for 20 minutes, the tensions induced by PE and Ang II were measured again. In the TARs without endothelium, the tensions induced by PE and Ang II were measured by the same method. RESULTS: In the TARs with endothelium, the tension of relaxation induced by cumulative doses of Ach and A23187 decreased significantly in 8 h and 16h groups. The tension of contraction induced by cumulative doses of PE and Ang II also decreased significantly (P<0.05). The tension of contraction increased after the preincubation with L-NNA. In the TARs without endothelium, the tension of contraction induced by PE and Ang II increased comparing to that of TARs with endothelium. CONCLUSION The soft tissue crush injury can influence the tensions of TARs in rats and the vascular-derived NO can mediate the effects.
Animals ; Aorta, Thoracic/physiopathology* ; Disease Models, Animal ; Endothelium, Vascular/metabolism* ; Female ; Hindlimb/injuries* ; Male ; Muscle, Smooth, Vascular/metabolism* ; NG-Nitroarginine Methyl Ester/pharmacology* ; Nitric Oxide/biosynthesis* ; Nitric Oxide Synthase/metabolism* ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Soft Tissue Injuries/physiopathology* ; Vasoconstriction/drug effects* ; Vasoconstrictor Agents/pharmacology* ; Vasodilation/drug effects* ; Vasodilator Agents/pharmacology*

OBJECTIVETo investigate 7 gene expression profile associated with inflammation and oxidative stress in vascular endothelium injure of rats with deficiency of vital energy or qi stagnation, and the effect of Tongxinluo on gene expression profile.

METHODThe model of vascular endothelium injury of rats with deficiency of vital energy or qi stagnation were established by using high L-methionine, with load-carrying swimming or being fastened, respectively. RT-PCR and SAGE database which is available in NCBI, were used to analyze the changes of 7 gene expression related with inflammation and oxidative stress in endothelium injure and the effect of Tongxinluo on the gene expression profile.

RESULTCompared with control group, the gene expression of inflammation related COX-1, COX-2, oxidative stress related iNOS, SOD and blood vessel vasomotion related eNOS, ECE, increased in deficiency of vital energy group (P < 0.05 or P < 0.01), and the gene expression decreased with Tongxinluo treatment (P < 0.05 or P < 0.01). The gene expression of COX-1, COX-2, iNOS and eNOS, ECE, increased (P < 0.01), but the gene expression of PCS and SOD decreased (P < 0.01), in qi stagnation group, and the disorder of gene expression improved with treatment of Tongxinluo (P < 0.01).

CONCLUSIONThe 7 gene expression related to vascular endothelium injure were not the same in rat with deficiency of vital energy or qi stagnation, and Tongxinluo could regulate the disorder of the gene expression, protecting vascular endothelium from injure.

Animals ; Aspartic Acid Endopeptidases ; genetics ; Cyclooxygenase 1 ; genetics ; Cyclooxygenase 2 ; genetics ; Drug Combinations ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; Endothelin-Converting Enzymes ; Endothelium, Vascular ; injuries ; physiopathology ; Gene Expression ; drug effects ; Gene Expression Profiling ; Male ; Medicine, Chinese Traditional ; Metalloendopeptidases ; genetics ; Nitric Oxide Synthase Type II ; genetics ; Nitric Oxide Synthase Type III ; genetics ; metabolism ; Qi ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; Superoxide Dismutase ; genetics