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Harmful health effects of exposure to low-frequency noise (LFN) defined as noise with frequencies at ≤100 Hz on the circulatory system have been a concern. However, there has been no study on the effects of exposure to LFN on the circulatory system with consideration of its frequencies and decibels. In this study, the effects of short-term exposure to broad-band LFNs and their pure-tone components (pure-tone LFNs) on cutaneous blood flow in the extremities including the hands were investigated. In our fieldwork study, we first sampled some kinds of common broad-band LFNs. Our human study then showed that broad-band LFN with a narrower frequency range more strongly increased cutaneous blood flow than did broad-band LFN with a wider frequency range. Pure-tone LFNs of 70–100 Hz at ≤85 dB(Z), but not pure-tone LFNs exceeding 100 Hz, further increased levels of cutaneous blood flow. Our wavelet-transform spectrum analysis of cutaneous blood flow next revealed that the nitric oxide (NO)-dependent and -independent vascular activities of the vascular endothelium were specifically increased by exposure to pure-tone LFN. Our animal study again indicated that exposure to pure-tone LFN increased cutaneous blood flow in mice with impairments of bilateral inner ears as well as cutaneous blood flow in control mice, suggesting a limited effect of inner ear function on the LFN-mediated increase in cutaneous blood flow. The NO-dependent suppressive effect of pure-tone LFN on cutaneous blood flow was confirmed by inhibition of vascular endothelial activity through intravenous injection of an NO inhibitor in wild-type mice. Taken together, the results of this study demonstrated that the vascular endothelium is a target tissue of LFN and that NO is an effector of the LFN-mediated increase in cutaneous blood flow. Since improvement of peripheral circulation could generally promote human health, short-term exposure to LFN may be beneficial for health.

Hypertensive disorders of pregnancy, including preeclampsia, are one of the leading causes of maternal, fetal, and neonatal morbidity and mortality worldwide. In recent years, given the increase in the incidence of cardiovascular diseases in women of reproductive age and in the pediatric population, a series of studies have been conducted that have managed to capture the association between a history of preeclampsia and the development of cardiovascular diseases in women and fetuses years after the event, thus changing the thought that the entity culminates at the moment in which the placental tissue is expelled. “Preeclampsia, future cardiovascular risk factor in mothers and offspring?”, it is established as a bibliographic review focused on this cardiovascular risk factor and the impact it generates on the quality of life not only in women with a history of the disease, but also in their offspring; as well as the essential work that medical staff have to face in order to build effective therapeutic measures that manage to reduce or even mitigate the development of cardiovascular pathologies in these people., Los trastornos hipertensivos del embarazo, incluyendo a la preeclampsia, son una de las principales causas de la morbimortalidad materna, fetal y neonatal a nivel mundial. En los últimos años, ante el aumento en la incidencia de enfermedades de tipo cardiovascular en mujeres en edad reproductiva y en la población pediátrica, se ha conducido una serie de estudios que han logrado plasmar la asociación entre el antecedente de preeclampsia y el desarrollo de enfermedades cardiovasculares en las mujeres y los fetos años después del evento, cambiando así el pensamiento de que la entidad culmina en el momento cuando se expulsa el tejido placentario. “Preeclampsia, ¿factor de riesgo cardiovascular a futuro en madres y descendencia?”, se establece como una revisión de tipo bibliográfica enfocada en dicho factor de riesgo cardiovascular y el impacto que genera en la calidad de vida no solo en las mujeres con historia de la enfermedad, sino que también en la de su descendencia; así como la imprescindible labor a la que se enfrenta el personal médico ante la necesidad de edificar medidas terapéuticas efectivas que logren disminuir o incluso mitigar el desarrollo de patologías cardiovasculares en estas personas.

The vascular endothelium supplies nutrients and oxygen to different body organs and supports the progression of diseases such as cancer through angiogenesis. Pathological angiogenesis remains a challenge as most patients develop resistance to the approved anti-angiogenic therapies. Therefore, a better understanding of endothelium signaling will support the development of more effective treatments. Over the past two decades, the emerging consensus suggests that the role of endothelial cells in tumor development has gone beyond angiogenesis. Instead, endothelial cells are now considered active participants in the tumor microenvironment, secreting angiocrine factors such as cytokines, growth factors, and chemokines, which instruct their proximate microenvironments. The function of angiocrine signaling is being uncovered in different fields, such as tissue homeostasis, early development, organogenesis, organ regeneration post-injury, and tumorigenesis. In this review, we elucidate the intricate role of angiocrine signaling in cancer progression, including distant metastasis, tumor dormancy, pre-metastatic niche formation, immune evasion, and therapy resistance.

source:European journal of pharmacology. 2007, 567(1-2), 139–144, source:http://www.sciencedirect.com/science/article/pii/S0014299907004682

Upregulation of Notch signaling is associated with brain arteriovenous malformation (bAVM), a disease that lacks pharmacological treatments. Tetracycline (tet)-regulatable endothelial expression of constitutively active Notch4 (Notch4*tetEC) from birth induced bAVMs in 100% of mice by P16. To test whether targeting downstream signaling, while sustaining the causal Notch4*tetEC expression, induces AVM normalization, we deleted Rbpj, a mediator of Notch signaling, in endothelium from P16, by combining tet-repressible Notch4*tetEC with tamoxifen-inducible Rbpj deletion. Established pathologies, including AV connection diameter, AV shunting, vessel tortuosity, intracerebral hemorrhage, tissue hypoxia, life expectancy, and arterial marker expression were improved, compared with Notch4*tetEC mice without Rbpj deletion. Similarly, Rbpj deletion from P21 induced advanced bAVM regression. After complete AVM normalization induced by repression of Notch4*tetEC, virtually no bAVM relapsed, despite Notch4*tetEC re-expression in adults. Thus, inhibition of endothelial Rbpj halted Notch4*tetEC bAVM progression, normalized bAVM abnormalities, and restored microcirculation, providing proof of concept for targeting a downstream mediator to treat AVM pathologies despite a sustained causal molecular lesion.

Background Pulmonary arterial hypertension (PAH) is a complex, fatal disease where disease severity has been associated with the single nucleotide polymorphism (SNP) rs2856830, located near the human leukocyte antigen DPA1 (HLA-DPA1) gene. We aimed to define the genetic architecture of functional variants associated with PAH disease severity by identifying allele-specific binding transcription factors and downstream targets that control endothelial pathophenotypes and PAH. Methods and Results Electrophoretic mobility shift assays of oligonucleotides containing SNP rs2856830 and 8 SNPs in linkage disequilibrium revealed functional SNPs via allele-imbalanced binding to human pulmonary arterial endothelial cell nuclear proteins. DNA pulldown proteomics identified SNP-binding proteins. SNP genotyping and clinical correlation analysis were performed in 84 patients with PAH at University of Pittsburgh Medical Center and in 679 patients with PAH in the All of Us database. SNP rs9277336 was identified as a functional SNP in linkage disequilibrium (r2>0.8) defined by rs2856830, and the minor allele was associated with decreased hospitalizations and improved cardiac output in patients with PAH, an index of disease severity. SNP pulldown proteomics showed allele-specific binding of nuclear ACTN4 (alpha actinin 4) protein to rs9277336 minor allele. Both ACTN4 and HLA-DPA1 were downregulated in pulmonary endothelium in human patients and rodent models of PAH. Via transcriptomic and phenotypic analyses, knockdown of HLA-DPA1 phenocopied knockdown of ACTN4, both similarly controlling cell structure pathways, immune pathways, and endothelial dysfunction. Conclusions We defined the pathogenic activity of functional SNP rs9277336, entailing the allele-specific binding of ACTN4 and controlling expression of the neighboring HLA-DPA1 gene. Through inflammatory or genetic means, downregulation of this ACTN4-HLA-DPA1 regulatory axis promotes endothelial pathophenotypes, providing a mec

Elevated levels of cholesterol in the blood can induce endothelial dysfunction, a condition characterized by impaired nitric oxide production and decreased vasodilatory capacity. Endothelial dysfunction can promote vascular disease, such as atherosclerosis, where macrophages accumulate in the vascular intima and fatty plaques form that impair normal blood flow in conduit arteries. Current pharmacological strategies to treat atherosclerosis mostly focus on lipid lowering to prevent high levels of plasma cholesterol that induce endothelial dysfunction and atherosclerosis. While this approach is effective for most patients with atherosclerosis, for some, lipid lowering is not enough to reduce their cardiovascular risk factors associated with atherosclerosis (e.g., hypertension, cardiac dysfunction, stroke, etc.). For such patients, additional strategies targeted at reducing endothelial dysfunction may be beneficial. One novel strategy to restore endothelial function and mitigate atherosclerosis risk is to enhance the activity of Ca2+-activated K+ (KCa) channels in the endothelium with positive gating modulator drugs. Here, we review the mechanism of action of these small molecules and discuss their ability to improve endothelial function. We then explore how this strategy could mitigate endothelial dysfunction in the context of atherosclerosis by examining how KCa modulators can improve cardiovascular function in other settings, such as aging and type 2 diabetes. Finally, we consider questions that will need to be addressed to determine whether KCa channel activation could be used as a long-term add-on to lipid lowering to augment atherosclerosis treatment, particularly in patients where lipid-lowering is not adequate to improve their cardiovascular health.

Environmental cues, such as physical forces and heterotypic cell interactions play a critical role in cell function, yet their collective contributions to transcriptional changes are unclear. Focusing on human endothelial cells, we performed broad individual sample analysis to identify transcriptional drifts associated with environmental changes that were independent of genetic background. Global gene expression profiling by RNA sequencing and protein expression by liquid chromatography-mass spectrometry directed proteomics distinguished endothelial cells in vivo from genetically matched culture (in vitro) samples. Over 43% of the transcriptome was significantly changed by the in vitro environment. Subjecting cultured cells to long-term shear stress significantly rescued the expression of approximately 17% of genes. Inclusion of heterotypic interactions by co-culture of endothelial cells with smooth muscle cells normalized approximately 9% of the original in vivo signature. We also identified novel flow dependent genes, as well as genes that necessitate heterotypic cell interactions to mimic the in vivo transcriptome. Our findings highlight specific genes and pathways that rely on contextual information for adequate expression from those that are agnostic of such environmental cues.

PurposeThere is a pressing need to investigate the impact of type II diabetes mellitus on the posterior cornea in donor tissues given its increasing prevalence and potential impact on endothelial keratoplasty surgical outcomes.MethodsImmortalized human cultured corneal endothelial cells (CECs; HCEC-B4G12) were grown in hyperglycemic media for 2 weeks. Extracellular matrix (ECM) adhesive glycoprotein expression and advanced glycation end products (AGEs) in cultured cells and corneoscleral donor tissues, as well as the elastic modulus for the Descemet membrane (DMs) and CECs of diabetic and nondiabetic donor corneas, were measured.ResultsIn CEC cultures, increasing hyperglycemia resulted in increased transforming growth factor beta-induced (TGFBI) protein expression and colocalization with AGEs in the ECM. In donor corneas, the thicknesses of the DM and the interfacial matrix (IFM) between the DM and stroma both increased from 8.42 ± 1.35 µm and 0.504 ± 0.13 µm in normal corneas, respectively, to 11.13 ± 2.91 µm (DM) and 0.681 ± 0.24 µm (IFM) in non-advanced diabetes (P = 0.013 and P = 0.075, respectively) and 11.31 ± 1.76 µm (DM) and 0.744 ± 0.18 µm (IFM) in advanced diabetes (AD; P = 0.0002 and P = 0.003, respectively). Immunofluorescence in AD tissues versus controls showed increased AGEs (P < 0.001) and markedly increased labeling intensity for adhesive glycoproteins, including TGFBI, that colocalized with AGEs. The elastic modulus significantly increased between AD and control tissues for the DMs (P < 0.0001) and CECs (P < 0.0001).ConclusionsDiabetes and hyperglycemia alter human CEC ECM structure and composition, likely contributing to previously documented complications of endothelial keratoplasty using diabetic donor tissue, including tearing during graft preparation and reduced graft survival. AGE accumulation in the DM and IFM may be a useful biomarker for determining diabetic impact on posterior corneal tissue.

PurposeWe sought to define the role of Wwtr1 in murine ocular structure and function and determine the role of mechanotransduction in Fuchs' endothelial corneal dystrophy (FECD), with emphasis on interactions between corneal endothelial cells (CEnCs) and Descemet's membrane (DM).MethodsA Wwtr1 deficient mouse colony was established, and advanced ocular imaging, atomic force microscope (AFM), and histology/immunofluorescence were performed. Corneal endothelial wound healing was assessed using cryoinjury and phototherapeutic keratectomy in Wwtr1 deficient mice. Expression of WWTR1/TAZ was determined in the corneal endothelium from normal and FECD-affected patients; WWTR1 was screened for coding sequence variants in this FECD cohort.ResultsMice deficient in Wwtr1 had reduced CEnC density, abnormal CEnC morphology, softer DM, and thinner corneas versus wildtype controls by 2 months of age. Additionally, CEnCs had altered expression and localization of Na/K-ATPase and ZO-1. Further, Wwtr1 deficient mice had impaired CEnC wound healing. The WWTR1 transcript was highly expressed in healthy human CEnCs comparable to other genes implicated in FECD pathogenesis. Although WWTR1 mRNA expression was comparable between healthy and FECD-affected patients, WWTR1/TAZ protein concentrations were higher and localized to the nucleus surrounding guttae. No genetic associations were found in WWTR1 and FECD in a patient cohort compared to controls.ConclusionsThere are common phenotypic abnormalities seen between Wwtr1 deficient and FECD-affected patients, suggesting that Wwtr1 deficient mice could function as a murine model of late-onset FECD. Despite the lack of a genetic association between FECD and WWTR1, aberrant WWTR1/TAZ protein subcellular localization and degradation may play critical roles in the pathogenesis of FECD.

The intestinal barrier, with its multiple layers, is the first line of defense between the outside world and the intestine. Its disruption, resulting in increased intestinal permeability, is a recognized pathogenic factor of intestinal and extra-intestinal diseases. The identification of a gut-vascular barrier (GVB), consisting of a structured endothelium below the epithelial layer, has led to new evidence on the etiology and management of diseases of the gut-liver axis and the gut-brain axis, with recent implications in oncology as well. The gut-brain axis is involved in several neuroinflammatory processes. In particular, the recent description of a choroid plexus vascular barrier regulating brain permeability under conditions of gut inflammation identifies the endothelium as a key regulator in maintaining tissue homeostasis and health.

Baseline levels of endotheliopathy are associated with worse respiratory outcomes and mortality in undifferentiated acute respiratory failure (ARF), but knowledge is lacking on the development of endotheliopathy over time in ARF. We, therefore, aimed to evaluate the prognostic significance of trajectories of endotheliopathy during the first days of ARF. We performed a secondary, exploratory analysis of a single-center prospective cohort including 459 patients requiring mechanical ventilation. Based on Days 1–3 Syndecan-1, soluble Thrombomodulin (sTM), and Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), we divided patients into subgroups using latent class mixed modeling and correlated subgroups with clinical outcomes using Cox regression. Based on Syndecan-1 and sTM, respectively, we identified two subgroups. Based on PECAM-1, we identified three subgroups. Subgroups based on Syndecan-1 and sTM were identifiable from the baseline levels, but subgroups based on PECAM-1 were not. Patients with persistently high levels of both sTM and PECAM-1 were liberated from mechanical ventilation more slowly (Group high vs. Group low, sTM: hazard ratio [HR]: 0.66, 95% confidence interval [CI]: 0.50–0.88, p =.01, PECAM-1: HR: 0.59, 95% CI: 0.37–0.93, p =.02) and had higher 30-day mortality (sTM: HR: 1.90, 95% CI: 1.20–3.01, p =.01, PECAM-1: HR: 4.25, 95% CI: 1.99–9.07, p <.01). In ARF requiring mechanical ventilation, patients in subgroups with persistently high levels of sTM and PECAM-1 had lower rates of liberation from mechanical ventilation and higher 30-day mortality. However, patients with persistently high levels of sTM were identifiable based on the baseline level, and only the trajectory of PECAM-1 added information to that of the baseline level.

Background: Acute cardiovascular stress increases systemic wall shear stress (WSS)–a frictional force exerted by the flow of blood on vessel walls–which raises plasma nitrite concentration due to enhanced endothelial nitric oxide synthase (eNOS) activity. Upstream eNOS inhibition modulates distal perfusion, and autonomic stress increases both the consumption and vasodilatory effects of endogenous nitrite. Plasma nitrite maintains vascular homeostasis during exercise and disruption of nitrite bioavailability can lead to intermittent claudication. Hypothesis: During acute cardiovascular stress or strenuous exercise, we hypothesize enhanced production of nitric oxide (NO) by vascular endothelial cells raises nitrite concentrations in near-wall layers of flowing blood, resulting in cumulative NO concentrations in downstream arterioles sufficient for vasodilation. Confirmation and implications: Utilizing a multiscale model of nitrite transport in bifurcating arteries, we tested the hypothesis for femoral artery flow under resting and exercised states of cardiovascular stress. Results indicate intravascular transport of nitrite from upstream endothelium could result in vasodilator-active levels of nitrite in downstream resistance vessels. The hypothesis could be confirmed utilizing artery-on-a-chip technology to measure NO production rates directly and help validate numerical model predictions. Further characterization of this mechanism may improve our understanding of symptomatic peripheral artery occlusive disease and exercise physiology.

BACKGROUND: Patients with kidney failure have a high risk for cardiovascular events. We aimed to evaluate the prognostic importance of selected biomarkers related to haemostasis, endothelial function, and vascular regulation in patients with acute coronary syndrome (ACS), and to study whether this association differed in patients with renal dysfunction. METHODS: Plasma was collected in 1370 ACS patients included between 2008 and 2015. Biomarkers were analysed using a Proximity Extension Assay and a Multiple Reaction Monitoring mass spectrometry assay. To reduce multiplicity, biomarkers correlating with eGFR were selected a priori among 36 plasma biomarkers reflecting endothelial and vascular function, and haemostasis. Adjusted Cox regression were used to study their association with the composite outcome of myocardial infarction, ischemic stroke, heart failure or death. Interaction with eGFR strata above or below 60 ml/min/1.73 m2 was tested. RESULTS: Tissue factor, proteinase-activated receptor, soluble urokinase plasminogen activator surface receptor (suPAR), thrombomodulin, adrenomedullin, renin, and angiotensinogen correlated inversely with eGFR and were selected for the Cox regression. Mean follow-up was 5.2 years during which 428 events occurred. Adrenomedullin, suPAR, and renin were independently associated with the composite outcome. Adrenomedullin showed interaction with eGFR strata (p = 0.010) and was associated with increased risk (HR 1.88; CI 1.44-2.45) only in patients with eGFR ≥60 ml/min/ 1.73 m2. CONCLUSIONS: Adrenomedullin, suPAR, and renin were associated with the composite outcome in all. Adrenomedullin, involved in endothelial protection, showed a significant interaction with renal function and outcome, and was associated with the composite outcome only in patients with preserved kidney function.

Hemorrhagic shock causes an immediate decrease in microcirculatory perfusion, which cannot be restored by standard therapy with fluids and blood products. The disturbance in microcirculatory perfusion is suggested to be the underlying cause of multiple organ failure, leading to increased mortality. To date, additional treatment strategies to restore microcirculatory perfusion following hemorrhagic shock are lacking. The endothelium is a semi-permeable barrier that covers the inner layer of the microvasculature, where it tightly regulates the exchange of fluids, nutrients and waste products between blood and tissue. In this thesis, we propose the microvascular endothelium as central regulator of hemorrhagic shock-induced microcirculatory perfusion disturbances. We investigated the effect of hemorrhagic shock and fluid resuscitation on endothelial barrier function and microcirculatory perfusion. Subsequently, we investigated which molecular mechanisms are of interest as target to reduce microvascular leakage and restore microcirculatory perfusion following hemorrhagic shock. Due to the central role of the endothelium, we propose the endothelial angiopoietin/Tie2 system, a key regulator of endothelial barrier function, as target to reduce microvascular leakage following hemorrhagic shock. The angiopoietin/Tie2 system consists of several components, of which the ligands angiopoietin-1 and angiopoietin-2 and the Tie2 receptor are mostly investigated. Under healthy conditions, angiopoietin-1 binds to the Tie2 receptor which subsequently leads to activation of the downstream pathway, thereby maintaining endothelial barrier function. A stress response, such as inflammation, excessively releases angiopoietin-2 which competitively binds the Tie2 receptor, blocking activation of the Tie2 receptor and disrupting endothelial barrier function. In this thesis, we investigated the effect of dysregulation of the angiopoietin/Tie2 system on microvascular integrity in mice. Subsequent

Pulmonary thromboembolism is the partial or complete obstruction of a pulmonary artery or arteries as a result of the migration of a clot formed mainly in the pelvic limbs, although it can occasionally come from the thoracic limbs, especially in patients with venous catheters. The methodology used for this research work is part of a documentary-type bibliographic review, since we are going to deal with issues raised at a theoretical level, such as Pulmonary Embolism in Covid. The technique for data collection is made up of electronic materials, the latter such as Google Scholar, PubMed, Science direct, among others, relying for this on the use of descriptors in health sciences or MESH terminology. The information obtained here will be reviewed for further analysis. Despite the fact that Covid causes a systemic inflammatory response and endothelial damage that generates a state of hypercoagulability, with an increase in thrombin and a decrease in natural anticoagulants, predisposing patients to thrombotic phenomena of venous and arterial location, and that in many studies this pathology has been present in patients with negative and positive PCR tests for Covid 19, it requires new studies to confirm that high levels of D-dimer and great involvement of the lung parenchyma are triggers of pulmonary embolism. Imaging tests such as CT angiography are essential to detect patients with pulmonary thromboembolism, as well as its degree, prognosis and treatment., La tromboembolia pulmonar es la obstrucción parcial o completa de una arteria o arterias pulmonares como consecuencia de la migración de un coágulo formado principalmente en miembros pélvicos, aunque ocasionalmente puede provenir de los torácicos, sobre todo en enfermos con catéteres venosos. La metodología utilizada para el presente trabajo de investigación, se enmarca dentro de una revisión bibliográfica de tipo documental, ya que nos vamos a ocupar de temas planteados a nivel teórico como es Embolismo pulmonar en Covid. La técnica para la recolección de datos está constituida por materiales electrónicos, estos últimos como Google Académico, PubMed, Science direct, entre otros, apoyándose para ello en el uso de descriptores en ciencias de la salud o terminología MESH. La información aquí obtenida será revisada para su posterior análisis. A pesar que el Covid causa una respuesta inflamatoria sistémica y daño endotelial que genera un estado de hipercoagulabilidad, con aumento de trombina y disminución de los anticoagulantes naturales, predisponiendo a los pacientes a fenómenos trombóticos de localización venosa y arterial, y que en muchos estudios esta patología ha estado presente en pacientes con pruebas PCR negativas y positivas a Covid 19, requiere nuevos estudios, para confirmar que elevados niveles de dimero D y gran afectación del parénquima pulmonar son detonantes de embolismo pulmonar. Las pruebas de imágenes como la angio TC es fundamental para detectar los pacientes con tromboembolismo pulmonar, así como su grado, pronostico y tratamiento.

Pulmonary thromboembolism is the partial or complete obstruction of a pulmonary artery or arteries as a result of the migration of a clot formed mainly in the pelvic limbs, although it can occasionally come from the thoracic limbs, especially in patients with venous catheters. The methodology used for this research work is part of a documentary-type bibliographic review, since we are going to deal with issues raised at a theoretical level, such as Pulmonary Embolism in Covid. The technique for data collection is made up of electronic materials, the latter such as Google Scholar, PubMed, Science direct, among others, relying for this on the use of descriptors in health sciences or MESH terminology. The information obtained here will be reviewed for further analysis. Despite the fact that Covid causes a systemic inflammatory response and endothelial damage that generates a state of hypercoagulability, with an increase in thrombin and a decrease in natural anticoagulants, predisposing patients to thrombotic phenomena of venous and arterial location, and that in many studies this pathology has been present in patients with negative and positive PCR tests for Covid 19, it requires new studies to confirm that high levels of D-dimer and great involvement of the lung parenchyma are triggers of pulmonary embolism. Imaging tests such as CT angiography are essential to detect patients with pulmonary thromboembolism, as well as its degree, prognosis and treatment., La tromboembolia pulmonar es la obstrucción parcial o completa de una arteria o arterias pulmonares como consecuencia de la migración de un coágulo formado principalmente en miembros pélvicos, aunque ocasionalmente puede provenir de los torácicos, sobre todo en enfermos con catéteres venosos. La metodología utilizada para el presente trabajo de investigación, se enmarca dentro de una revisión bibliográfica de tipo documental, ya que nos vamos a ocupar de temas planteados a nivel teórico como es Embolismo pulmonar en Covid. La técnica para la recolección de datos está constituida por materiales electrónicos, estos últimos como Google Académico, PubMed, Science direct, entre otros, apoyándose para ello en el uso de descriptores en ciencias de la salud o terminología MESH. La información aquí obtenida será revisada para su posterior análisis. A pesar que el Covid causa una respuesta inflamatoria sistémica y daño endotelial que genera un estado de hipercoagulabilidad, con aumento de trombina y disminución de los anticoagulantes naturales, predisponiendo a los pacientes a fenómenos trombóticos de localización venosa y arterial, y que en muchos estudios esta patología ha estado presente en pacientes con pruebas PCR negativas y positivas a Covid 19, requiere nuevos estudios, para confirmar que elevados niveles de dimero D y gran afectación del parénquima pulmonar son detonantes de embolismo pulmonar. Las pruebas de imágenes como la angio TC es fundamental para detectar los pacientes con tromboembolismo pulmonar, así como su grado, pronostico y tratamiento.

ObjectiveTo describe the clinical findings, multimodal corneal imaging features and treatment in canine patients diagnosed with endotheliitis.Animals studiedFour canine patients met inclusion criteria for bilateral corneal disease with endothelial inflammation and secondary corneal edema that responded to topical anti-inflammatory treatment.MethodsThe patients selected underwent a complete ophthalmic examination with emphasis on the cornea including ultrasound pachymetry (USP), Fourier-domain optical coherence tomography (FD-OCT), in vivo confocal microscopy (IVCM), and digital slit lamp photography.ResultsAll patients in this study demonstrated thickened corneas due to edema with USP and FD-OCT. With IVCM, mild to severe polymegathism and pleomorphism of corneal endothelial cells, reduced endothelial cell density, hyperreflective keratic precipitates (KPs), and extracellular debris as well as hyporeflective pseudoguttata were observed. With FD-OCT, hyperreflective KPs were commonly observed on the inferior cornea. Clinical examination and advanced imaging results were consistent with a diagnosis of endotheliitis. All patients initially responded to topical anti-inflammatory treatment and required continued therapy; two patients also received topical netarsudil, a rho-associated coiled-coil kinase inhibitor.ConclusionEndotheliitis should be considered for canine patients with bilateral edema that is most severe in the inferior cornea. Careful inspection of Descemet's membrane-endothelial complex should be performed for KPs or inflammatory debris. Chronic administration of topical anti-inflammatories may be necessary to prevent flare-ups of endotheliitis.

Endothelial cells differ from other cell types responsible for the formation of the vascular wall in their unusual reliance on glycolysis for most energy needs, which results in extensive production of lactate. We find that endothelium-derived lactate is taken up by pericytes, and contributes substantially to pericyte metabolism including energy generation and amino acid biosynthesis. Endothelial-pericyte proximity is required to facilitate the transport of endothelium-derived lactate into pericytes. Inhibition of lactate production in the endothelium by deletion of the glucose transporter-1 (GLUT1) in mice results in loss of pericyte coverage in the retina and brain vasculatures, leading to the blood-brain barrier breakdown and increased permeability. These abnormalities can be largely restored by oral lactate administration. Our studies demonstrate an unexpected link between endothelial and pericyte metabolisms and the role of endothelial lactate production in the maintenance of the blood-brain barrier integrity. In addition, our observations indicate that lactate supplementation could be a useful therapeutic approach for GLUT1 deficiency metabolic syndrome patients.

The ontogeny of human haematopoietic stem cells (HSCs) is poorly defined owing to the inability to identify HSCs as they emerge and mature at different haematopoietic sites1. Here we created a single-cell transcriptome map of human haematopoietic tissues from the first trimester to birth and found that the HSC signature RUNX1+HOXA9+MLLT3+MECOM+HLF+SPINK2+ distinguishes HSCs from progenitors throughout gestation. In addition to the aorta-gonad-mesonephros region, nascent HSCs populated the placenta and yolk sac before colonizing the liver at 6 weeks. A comparison of HSCs at different maturation stages revealed the establishment of HSC transcription factor machinery after the emergence of HSCs, whereas their surface phenotype evolved throughout development. The HSC transition to the liver marked a molecular shift evidenced by suppression of surface antigens reflecting nascent HSC identity, and acquisition of the HSC maturity markers CD133 (encoded by PROM1) and HLA-DR. HSC origin was tracked to ALDH1A1+KCNK17+ haemogenic endothelial cells, which arose from an IL33+ALDH1A1+ arterial endothelial subset termed pre-haemogenic endothelial cells. Using spatial transcriptomics and immunofluorescence, we visualized this process in ventrally located intra-aortic haematopoietic clusters. The in vivo map of human HSC ontogeny validated the generation of aorta-gonad-mesonephros-like definitive haematopoietic stem and progenitor cells from human pluripotent stem cells, and serves as a guide to improve their maturation to functional HSCs.

ObjectiveFailure to close the ductus arteriosus, patent ductus arteriosus, accounts for 10% of all congenital heart defects. Despite significant advances in patent ductus arteriosus management, including pharmacological treatment targeting the prostaglandin pathway, a proportion of patients fail to respond and must undergo surgical intervention. Thus, further refinement of the cellular and molecular mechanisms that govern vascular remodeling of this vessel is required.MethodsWe performed single-cell RNA-sequencing of the ductus arteriosus in mouse embryos at E18.5 (embryonic day 18.5), and P0.5 (postnatal day 0.5), and P5 to identify transcriptional alterations that might be associated with remodeling. We further confirmed our findings using transgenic mouse models coupled with immunohistochemistry analysis.ResultsThe intermediate filament vimentin emerged as a candidate that might contribute to closure of the ductus arteriosus. Indeed, mice with genetic deletion of vimentin fail to complete vascular remodeling of the ductus arteriosus. To seek mechanisms, we turned to the RNA-sequencing data that indicated changes in Jagged1 with similar profile to vimentin and pointed to potential links with Notch. In fact, Notch3 signaling was impaired in vimentin null mice and vimentin null mice phenocopies patent ductus arteriosus in Jagged1 endothelial and smooth muscle deleted mice.ConclusionsThrough single-cell RNA-sequencing and by tracking closure of the ductus arteriosus in mice, we uncovered the unexpected contribution of vimentin in driving complete closure of the ductus arteriosus through a mechanism that includes deregulation of the Notch signaling pathway.

The obligate intracellular parasite Toxoplasma gondii makes use of infected leukocytes for systemic dissemination. Yet, how infection impacts the processes of leukocyte diapedesis has remained unresolved. Here, we addressed the effects of T. gondii infection on the trans-endothelial migration (TEM) of dendritic cells (DCs) across polarised brain endothelial monolayers. We report that upregulated expression of leukocyte ICAM-1 is a feature of the enhanced TEM of parasitised DCs. The secreted parasite effector GRA15 induced an elevated expression of ICAM-1 in infected DCs that was associated with enhanced cell adhesion and TEM. Consequently, gene silencing of Icam-1 in primary DCs or deletion of parasite GRA15 reduced TEM. Further, the parasite effector TgWIP, which impacts the regulation of host actin dynamics, facilitated TEM across polarised endothelium. The data highlight that the concerted action of the secreted effectors GRA15 and TgWIP modulate the leukocyte-endothelial interactions of TEM in a parasite genotype-related fashion to promote dissemination. In addition to the canonical roles of endothelial ICAM-1, this study identifies a previously unappreciated role for leukocyte ICAM-1 in infection-related TEM.

Renalase is a secreted flavoprotein with anti-inflammatory and pro-cell survival properties. COVID-19 is associated with disordered inflammation and apoptosis. We hypothesized that blood renalase levels would correspond to severe COVID-19 and survival. In this retrospective cohort study, clinicopathologic data and blood samples were collected from hospitalized COVID-19 subjects (March-June 2020) at a single institution tertiary hospital. Plasma renalase and cytokine levels were measured and clinical data abstracted from health records. Of 3,450 COVID-19 patients, 458 patients were enrolled. Patients were excluded if <18 years, or opted out of research. The primary composite outcome was intubation or death within 180 days. Secondary outcomes included mortality alone, intensive care unit admission, use of vasopressors, and CPR. Enrolled patients had mean age 64 years (SD±17), were 53% males, and 48% non-whites. Mean renalase levels was 14,108·4 ng/ml (SD±8,137 ng/ml). Compared to patients with high renalase, those with low renalase (< 8,922 ng/ml) were more likely to present with hypoxia, increased ICU admission (54% vs. 33%, p < 0.001), and cardiopulmonary resuscitation (10% vs. 4%, p = 0·023). In Cox proportional hazard model, every 1000 ng/ml increase in renalase decreased the risk of death or intubation by 5% (HR 0·95; 95% CI 0·91-0·98) and increased survival alone by 6% (HR 0·95; CI 0·90-0·98), after adjusting for socio-demographics, initial disease severity, comorbidities and inflammation. Patients with high renalase-low IL-6 levels had the best survival compared to other groups (p = 0·04). Renalase was independently associated with reduced intubation and mortality in hospitalized COVID-19 patients. Future studies should assess the pathophysiological relevance of renalase in COVID-19 disease.

Heterogeneity of endothelial cell (EC) populations reflects their diverse functions in maintaining tissues homeostasis. However, their phenotypic, molecular, and functional properties are not entirely mapped. We use the Tie2-CreERT2;Rosa26-tdTomato reporter mouse to trace, profile, and cultivate primary ECs from different organs. As paradigm platform, we use this strategy to study bone marrow endothelial cells (BMECs). Single-cell mRNA sequencing of primary BMECs reveals that their diversity and native molecular signatures is transitorily preserved in an ex vivo culture that conserves key cell-to-cell microenvironment interactions. Macrophages sustain BMEC cellular diversity and expansion and preserve sinusoidal-like BMECs ex vivo. Endomucin expression discriminates BMECs in populations exhibiting mutually exclusive properties and distinct sinusoidal/arterial and tip/stalk signatures. In contrast to arterial-like, sinusoidal-like BMECs are short-lived, form 2D-networks, contribute to in vivo angiogenesis, and support hematopoietic stem/progenitor cells in vitro. This platform can be extended to other organs ECs to decode mechanistic information and explore therapeutics.

Objectives Postoperative endothelial damage potentially results in increased vascular leakage, tissue edema and subsequent complications. The preventive effect of glucocorticoids on endothelial damage after surgery is sparsely described, including the relation between endothelial damage and the postoperative inflammatory response. Thus, we aimed to assess the preventive effect of high-dose glucocorticoids on postoperative endothelial damage, and the association between endothelial damage and inflammation after surgery. Methods This was a predefined substudy of a randomized double-blinded clinical trial of methylprednisolone 10 mg/kg (high dose) vs. dexamethasone 8 mg (low dose) in patients undergoing liver resection at Rigshospitalet, Copenhagen. In total 25 patients undergoing major liver resection (11 in the high-dose group and 14 in the low-dose group) were included. The primary outcome was changed in five endothelial biomarkers and the secondary outcome was changes in inflammation [C-reactive protein (CRP)] for the first three postoperative days. Results No statistically significant difference was found for any endothelial biomarkers postoperatively between the two groups (P > 0.15, for all). High-dose glucocorticoids significantly reduced CRP on day 3 compared to low-dose glucocorticoids [median difference on a postoperative day 3, 59.6 g/L, (84.2; 27.1), P < 0.002]. No significant correlation between endothelial damage and CRP levels was seen. Conclusions No significant effect of high- vs. low-dose glucocorticoids on development in endothelial biomarkers after major liver resection was observed. High-dose glucocorticoids reduce the inflammatory response though without correlation to endothelial damage. Future studies should assess the clinical impact of increased endothelial biomarkers for clinical perioperative outcomes.

Background: The endotheliopathy of trauma (EoT) is associated with increased mortality following injury. Herein, we describe the plasma proteome related to EoT in order to provide insight into the role of the endothelium within the systemic response to trauma. Methods: 99 subjects requiring the highest level of trauma activation were included in the study. Enzyme-linked immunosorbent assays of endothelial and catecholamine biomarkers were performed on admission plasma samples, as well as untargeted proteome quantification utilizing high-performance liquid chromatography and tandem mass spectrometry. Results: Plasma endothelial and catecholamine biomarker abundance was elevated in EoT. Patients with EoT (n = 62) had an increased incidence of death within 24 h at 21% compared to 3% for non-EoT (n = 37). Proteomic analysis revealed that 52 out of 290 proteins were differentially expressed between the EoT and non-EoT groups. These proteins are involved in endothelial activation, coagulation, inflammation, and oxidative stress, and include known damage-associated molecular patterns (DAMPs) and intracellular proteins specific to several organs. Conclusions: We report a proteomic profile of EoT suggestive of a surge of DAMPs and inflammation driving nonspecific activation of the endothelial, coagulation, and complement systems with subsequent end-organ damage and poor clinical outcome. These findings support the utility of EoT as an index of cellular injury and delineate protein candidates for therapeutic intervention.

Cerebral cavernous malformation (CCM) is a neurovascular disease that affects 0.5% of the general population. For a long time, CCM research focused on genetic mutations, endothelial junctions and proliferation, but recently, transcriptome and proteome studies have revealed that the hemostatic system and neuroinflammation play a crucial role in the development and severity of cavernomas, with some of these publications coming from our group. The aim of this review is to give an overview of the latest molecular insights into the interaction between CCM-deficient endothelial cells with blood components and the neurovascular unit. Specifically, we underscore how endothelial dysfunction can result in dysregulated hemostasis, bleeding, hypoxia and neurological symptoms. We conducted a thorough review of the literature and found a field that is increasingly poised to regard CCM as a hemostatic disease, which may have implications for therapy.

In preparation for tracheal intubation during induction of anesthesia, the patient may be ventilated with 100% oxygen. To investigate the impact of acute isocapnic hyperoxia on endothelial activation and vascular remodeling, ten healthy young men (24±3 years) were exposed to 5-min normoxia (21% O2) and 10-min hyperoxia trials (100% O2). During hyperoxia, intercellular adhesion molecules (ICAM-1) (hyperoxia: 4.16±0.85 vs normoxia: 3.51±0.84 ng/mL, P=0.04) and tissue inhibitor matrix metalloproteinase 1 (TIMP-1) (hyperoxia: 8.40±3.84 vs normoxia: 5.73±2.15 pg/mL, P=0.04) increased, whereas matrix metalloproteinase (MMP-9) activity (hyperoxia: 0.53±0.11 vs normoxia: 0.68±0.18 A.U., P=0.03) decreased compared to the normoxia trial. We concluded that even short exposure to 100% oxygen may affect endothelial activation and vascular remodeling.

Pulmonary thromboembolism is the partial or complete obstruction of a pulmonary artery or arteries as a result of the migration of a clot formed mainly in the pelvic limbs, although it can occasionally come from the thoracic limbs, especially in patients with venous catheters. The methodology used for this research work is part of a documentary-type bibliographic review, since we are going to deal with issues raised at a theoretical level, such as Pulmonary Embolism in Covid. The technique for data collection is made up of electronic materials, the latter such as Google Scholar, PubMed, Science direct, among others, relying for this on the use of descriptors in health sciences or MESH terminology. The information obtained here will be reviewed for further analysis. Despite the fact that Covid causes a systemic inflammatory response and endothelial damage that generates a state of hypercoagulability, with an increase in thrombin and a decrease in natural anticoagulants, predisposing patients to thrombotic phenomena of venous and arterial location, and that in many studies this pathology has been present in patients with negative and positive PCR tests for Covid 19, it requires new studies to confirm that high levels of D-dimer and great involvement of the lung parenchyma are triggers of pulmonary embolism. Imaging tests such as CT angiography are essential to detect patients with pulmonary thromboembolism, as well as its degree, prognosis and treatment., La tromboembolia pulmonar es la obstrucción parcial o completa de una arteria o arterias pulmonares como consecuencia de la migración de un coágulo formado principalmente en miembros pélvicos, aunque ocasionalmente puede provenir de los torácicos, sobre todo en enfermos con catéteres venosos. La metodología utilizada para el presente trabajo de investigación, se enmarca dentro de una revisión bibliográfica de tipo documental, ya que nos vamos a ocupar de temas planteados a nivel teórico como es Embolismo pulmonar en Covid. La técnica para la recolección de datos está constituida por materiales electrónicos, estos últimos como Google Académico, PubMed, Science direct, entre otros, apoyándose para ello en el uso de descriptores en ciencias de la salud o terminología MESH. La información aquí obtenida será revisada para su posterior análisis. A pesar que el Covid causa una respuesta inflamatoria sistémica y daño endotelial que genera un estado de hipercoagulabilidad, con aumento de trombina y disminución de los anticoagulantes naturales, predisponiendo a los pacientes a fenómenos trombóticos de localización venosa y arterial, y que en muchos estudios esta patología ha estado presente en pacientes con pruebas PCR negativas y positivas a Covid 19, requiere nuevos estudios, para confirmar que elevados niveles de dimero D y gran afectación del parénquima pulmonar son detonantes de embolismo pulmonar. Las pruebas de imágenes como la angio TC es fundamental para detectar los pacientes con tromboembolismo pulmonar, así como su grado, pronostico y tratamiento.

Pulmonary thromboembolism is the partial or complete obstruction of a pulmonary artery or arteries as a result of the migration of a clot formed mainly in the pelvic limbs, although it can occasionally come from the thoracic limbs, especially in patients with venous catheters. The methodology used for this research work is part of a documentary-type bibliographic review, since we are going to deal with issues raised at a theoretical level, such as Pulmonary Embolism in Covid. The technique for data collection is made up of electronic materials, the latter such as Google Scholar, PubMed, Science direct, among others, relying for this on the use of descriptors in health sciences or MESH terminology. The information obtained here will be reviewed for further analysis. Despite the fact that Covid causes a systemic inflammatory response and endothelial damage that generates a state of hypercoagulability, with an increase in thrombin and a decrease in natural anticoagulants, predisposing patients to thrombotic phenomena of venous and arterial location, and that in many studies this pathology has been present in patients with negative and positive PCR tests for Covid 19, it requires new studies to confirm that high levels of D-dimer and great involvement of the lung parenchyma are triggers of pulmonary embolism. Imaging tests such as CT angiography are essential to detect patients with pulmonary thromboembolism, as well as its degree, prognosis and treatment., La tromboembolia pulmonar es la obstrucción parcial o completa de una arteria o arterias pulmonares como consecuencia de la migración de un coágulo formado principalmente en miembros pélvicos, aunque ocasionalmente puede provenir de los torácicos, sobre todo en enfermos con catéteres venosos. La metodología utilizada para el presente trabajo de investigación, se enmarca dentro de una revisión bibliográfica de tipo documental, ya que nos vamos a ocupar de temas planteados a nivel teórico como es Embolismo pulmonar en Covid. La técnica para la recolección de datos está constituida por materiales electrónicos, estos últimos como Google Académico, PubMed, Science direct, entre otros, apoyándose para ello en el uso de descriptores en ciencias de la salud o terminología MESH. La información aquí obtenida será revisada para su posterior análisis. A pesar que el Covid causa una respuesta inflamatoria sistémica y daño endotelial que genera un estado de hipercoagulabilidad, con aumento de trombina y disminución de los anticoagulantes naturales, predisponiendo a los pacientes a fenómenos trombóticos de localización venosa y arterial, y que en muchos estudios esta patología ha estado presente en pacientes con pruebas PCR negativas y positivas a Covid 19, requiere nuevos estudios, para confirmar que elevados niveles de dimero D y gran afectación del parénquima pulmonar son detonantes de embolismo pulmonar. Las pruebas de imágenes como la angio TC es fundamental para detectar los pacientes con tromboembolismo pulmonar, así como su grado, pronostico y tratamiento.

Atherosclerosis is an inflammatory chronic illness characterized by the buildup of fats, cholesterol and other substances in and on the artery wall causing its hardening. This work presents a mathematical model that analyze the inflammatory stage of atherosclerosis. We present a system of four coupled type of partial differential equations. Four leading players are taken into consideration: LDL (L), oxidized LDL (Lox), immune cells (M ) and the pro-inflammatory cytokines (C). In addition, one characteristic parameter taken into account is the permeability of the endothelial layer. A stability analysis and existence proof for fixed points of the kinetic system is presented leading to a biological interpretation. We are able to distinguish three main cases of the disease state that correlates with the permeability of the endothelial layer; where we can note that the permeability is classified according to its value based on the remaining parameters. In fact, when the permeability is low, this case is considered to be the disease free state since no chronic inflammatory reaction occurs due to the non-initiation of the auto-amplification process. With intermediate permeability, a wave propagation corresponding to a chronic inflammatory reaction might happen, whether the initial perturbation overcome a threshold or not. With high permeability, even a small perturbation of the disease free state drives to a chronic inflammatory reaction represented by a wave propagation.

The tumour vasculature is well-established to display irregular structure and hierarchy that is conducive to promoting tumour growth and metastasis while maintaining immunosuppression. As tumours grow, their metabolic rate increases while their distance from blood vessels furthers, generating a hypoxic and acidic tumour microenvironment. Consequently, cancer cells upregulate the expression of pro-angiogenic factors which propagate aberrant blood vessel formation. This generates atypical vascular features that reduce chemotherapy, radiotherapy, and immunotherapy efficacy. Therefore, the development of therapies aiming to restore the vasculature to a functional state remains a necessary research target. Many anti-angiogenic therapies aim to target this such as bevacizumab or sunitinib but have shown variable efficacy in solid tumours due to intrinsic or acquired resistance. Therefore, novel therapeutic strategies such as combination therapies and nanotechnology-mediated therapies may provide alternatives to overcoming the barriers generated by the tumour vasculature. This review summarises the mechanisms that induce abnormal tumour angiogenesis and how the vasculature’s features elicit immunosuppression. Furthermore, the review explores examples of treatment regiments that target the tumour vasculature.

Cerebral cavernous malformation (CCM) is a neurovascular disease that affects 0.5% of the general population. For a long time, CCM research focused on genetic mutations, endothelial junctions and proliferation, but recently, transcriptome and proteome studies have revealed that the hemostatic system and neuroinflammation play a crucial role in the development and severity of cavernomas, with some of these publications coming from our group. The aim of this review is to give an overview of the latest molecular insights into the interaction between CCM-deficient endothelial cells with blood components and the neurovascular unit. Specifically, we underscore how endothelial dysfunction can result in dysregulated hemostasis, bleeding, hypoxia and neurological symptoms. We conducted a thorough review of the literature and found a field that is increasingly poised to regard CCM as a hemostatic disease, which may have implications for therapy.

Background: The endotheliopathy of trauma (EoT) is associated with increased mortality following injury. Herein, we describe the plasma proteome related to EoT in order to provide insight into the role of the endothelium within the systemic response to trauma. Methods: 99 subjects requiring the highest level of trauma activation were included in the study. Enzyme-linked immunosorbent assays of endothelial and catecholamine biomarkers were performed on admission plasma samples, as well as untargeted proteome quantification utilizing high-performance liquid chromatography and tandem mass spectrometry. Results: Plasma endothelial and catecholamine biomarker abundance was elevated in EoT. Patients with EoT (n = 62) had an increased incidence of death within 24 h at 21% compared to 3% for non-EoT (n = 37). Proteomic analysis revealed that 52 out of 290 proteins were differentially expressed between the EoT and non-EoT groups. These proteins are involved in endothelial activation, coagulation, inflammation, and oxidative stress, and include known damage-associated molecular patterns (DAMPs) and intracellular proteins specific to several organs. Conclusions: We report a proteomic profile of EoT suggestive of a surge of DAMPs and inflammation driving nonspecific activation of the endothelial, coagulation, and complement systems with subsequent end-organ damage and poor clinical outcome. These findings support the utility of EoT as an index of cellular injury and delineate protein candidates for therapeutic intervention.

The endotheliopathy of trauma (EoT) is associated with increased mortality following injury. Herein, we describe the plasma proteome related to EoT in order to provide insight into the role of the endothelium within the systemic response to trauma. 99 subjects requiring the highest level of trauma activation were included in the study. Enzyme-linked immunosorbent assays of endothelial and catecholamine biomarkers were performed on admission plasma samples, as well as untargeted proteome quantification utilizing high-performance liquid chromatography and tandem mass spectrometry. Plasma endothelial and catecholamine biomarker abundance was elevated in EoT. Patients with EoT (n = 62) had an increased incidence of death within 24 h at 21% compared to 3% for non-EoT (n = 37). Proteomic analysis revealed that 52 out of 290 proteins were differentially expressed between the EoT and non-EoT groups. These proteins are involved in endothelial activation, coagulation, inflammation, and oxidative stress, and include known damage-associated molecular patterns (DAMPs) and intracellular proteins specific to several organs. We report a proteomic profile of EoT suggestive of a surge of DAMPs and inflammation driving nonspecific activation of the endothelial, coagulation, and complement systems with subsequent end-organ damage and poor clinical outcome. These findings support the utility of EoT as an index of cellular injury and delineate protein candidates for therapeutic intervention.

Cerebral cavernous malformation (CCM) is a neurovascular disease that affects 0.5% of the general population. For a long time, CCM research focused on genetic mutations, endothelial junctions and proliferation, but recently, transcriptome and proteome studies have revealed that the hemostatic system and neuroinflammation play a crucial role in the development and severity of cavernomas, with some of these publications coming from our group. The aim of this review is to give an overview of the latest molecular insights into the interaction between CCM-deficient endothelial cells with blood components and the neurovascular unit. Specifically, we underscore how endothelial dysfunction can result in dysregulated hemostasis, bleeding, hypoxia and neurological symptoms. We conducted a thorough review of the literature and found a field that is increasingly poised to regard CCM as a hemostatic disease, which may have implications for therapy.

Cerebral cavernous malformation (CCM) is a neurovascular disease that affects 0.5% of the general population. For a long time, CCM research focused on genetic mutations, endothelial junctions and proliferation, but recently, transcriptome and proteome studies have revealed that the hemostatic system and neuroinflammation play a crucial role in the development and severity of cavernomas, with some of these publications coming from our group. The aim of this review is to give an overview of the latest molecular insights into the interaction between CCM-deficient endothelial cells with blood components and the neurovascular unit. Specifically, we underscore how endothelial dysfunction can result in dysregulated hemostasis, bleeding, hypoxia and neurological symptoms. We conducted a thorough review of the literature and found a field that is increasingly poised to regard CCM as a hemostatic disease, which may have implications for therapy.

Cerebral cavernous malformation (CCM) is a neurovascular disease that affects 0.5% of the general population. For a long time, CCM research focused on genetic mutations, endothelial junctions and proliferation, but recently, transcriptome and proteome studies have revealed that the hemostatic system and neuroinflammation play a crucial role in the development and severity of cavernomas, with some of these publications coming from our group. The aim of this review is to give an overview of the latest molecular insights into the interaction between CCM-deficient endothelial cells with blood components and the neurovascular unit. Specifically, we underscore how endothelial dysfunction can result in dysregulated hemostasis, bleeding, hypoxia and neurological symptoms. We conducted a thorough review of the literature and found a field that is increasingly poised to regard CCM as a hemostatic disease, which may have implications for therapy.

The coronavirus disease 2019 (COVID-19) infected so far over 250 million people and caused the death of over 5 million worldwide. Aging, diabetes, and cardiovascular diseases, conditions with preexisting impaired endothelial functions predispose to COVID-19. While respiratory epithelium is the main route of virus entry, the endothelial cells (ECs) lining pulmonary blood vessels are also an integral part of lung injury in COVID-19 patients. COVID-19 not only affects the lungs and respiratory system but also gastrointestinal (GI) tract, liver, pancreas, kidneys, heart, brain, and skin. Blood vessels are likely conduits for the virus dissemination to these distant organs. Importantly, ECs are also critical for vascular regeneration during injury/lesions healing and restoration of vascular network. The World Journal of Gastroenterology has published in last two years over 67 outstanding papers on COVID-19 infection with a focus on the GI tract, liver, pancreas, etc., however, the role of the endothelial and vascular components as major targets for COVID-19-induced tissue injury, spreading to various organs, and injury healing have not been sufficiently emphasized. In the present article, we focus on these subjects and on current treatments including the most recent oral drugs molnupiravir and paxlovid that show a dramatic, significant efficacy in controlling severe COVID-19 infection.

Angiogenesis is vital during pregnancy for remodeling and enhancing vasodilation of maternal uterine arteries, and increasing uterine blood flow. Abnormal angiogenesis is associated with decreased uteroplacental blood flow and development of pregnancy disorders such as gestational hypertension, preeclampsia, fetal growth restriction, preterm delivery, stillbirth, and miscarriage. The mechanisms that contribute to normal angiogenesis remain obscure. Our previous studies demonstrated that expression of the angiotensin type 2 receptor (AT2R) is increased while the angiotensin type 1 receptor (AT1R) is unchanged in the endothelium of uterine arteries, and that AT2R-mediated pregnancy adaptation facilitates enhanced vasodilation and uterine arterial blood flow. However, the role of AT2R in regulating angiogenesis during pregnancy has never been studied. This study examines whether or not AT2R activation induces angiogenesis and, if so, what mechanisms are involved. To this end, we used primary human uterine artery endothelial cells (hUAECs) isolated from pregnant and nonpregnant women undergoing hysterectomy. The present study shows that Compound 21, a selective AT2R agonist, induced proliferation of pregnant-hUAECs, but not nonpregnant-hUAECs, in a concentration-dependent manner, and that this C21-induced mitogenic effect was blocked by PD123319, a selective AT2R antagonist. The mitogenic effects induced by C21 were inhibited by blocking JNK-but not ERK, PI3K, and p38-signaling pathways. In addition, C21 concentration dependently increased cell migration and capillary-like tube formation in pregnant-hUAECs. The membrane-based antibody array showed that C21 increased expression of multiple angiogenic proteins, including EGF, bFGF, leptin, PLGF, IGF-1, and angiopoietins. Our qPCR analysis demonstrates that C21-induced increase in expression of these angiogenic proteins correlates with a proportional increase in mRNA expression, indicating that AT2R activates angiogenic pr

Clinically used inhibitors of mammalian target of rapamycin (mTOR) negatively impacts endothelial-dependent vasodilatation (EDD) through unidentified mechanisms. Here we show that either the endothelium-specific deletion of Mtor to inhibit both mTOR complexes, or depletion of Raptor or Rictor to disrupt mTORC1 or mTORC2, causes impaired EDD, accompanied by reduced NO in the serum of mice. Consistently, inhibition of mTOR decreases NO production by human and mouse EC. Specifically, inhibition of mTORC1 suppresses eNOS gene expression, due to impairment in p70S6K-mediated posttranscriptional regulation of the transcription factor KLF2 expression. In contrast to mTORC1 inhibition, a positive-feedback between MAPK (p38 and JNK) activation and Nox2 upregulation contributes to the excessive generation of reactive oxygen species (ROS), which causes eNOS uncoupling and decreased NO bioavailability in mTORC2-inhibited EC. Adeno-associated virus-mediated EC-specific overexpression of KLF2 or suppression of Nox2 restores EDD function in endothelial mTORC1- or mTORC2-inhibited mice.

Endothelial and erythropoietic lineages arise from a common developmental progenitor. Etv2 is a master transcriptional regulator required for the development of both lineages. However, the mechanisms through which Etv2 initiates the gene-regulatory networks (GRNs) for endothelial and erythropoietic specification and how the two GRNs diverge downstream of Etv2 remain incompletely understood. Here, by analyzing a hypomorphic Etv2 mutant, we demonstrate different threshold requirements for initiation of the downstream GRNs for endothelial and erythropoietic development. We show that Etv2 functions directly in a coherent feedforward transcriptional network for vascular endothelial development, and a low level of Etv2 expression is sufficient to induce and sustain the endothelial GRN. In contrast, Etv2 induces the erythropoietic GRN indirectly via activation of Tal1, which requires a significantly higher threshold of Etv2 to initiate and sustain erythropoietic development. These results provide important mechanistic insight into the divergence of the endothelial and erythropoietic lineages.

Pulmonary thromboembolism is the partial or complete obstruction of a pulmonary artery or arteries as a result of the migration of a clot formed mainly in the pelvic limbs, although it can occasionally come from the thoracic limbs, especially in patients with venous catheters. The methodology used for this research work is part of a documentary-type bibliographic review, since we are going to deal with issues raised at a theoretical level, such as Pulmonary Embolism in Covid. The technique for data collection is made up of electronic materials, the latter such as Google Scholar, PubMed, Science direct, among others, relying for this on the use of descriptors in health sciences or MESH terminology. The information obtained here will be reviewed for further analysis. Despite the fact that Covid causes a systemic inflammatory response and endothelial damage that generates a state of hypercoagulability, with an increase in thrombin and a decrease in natural anticoagulants, predisposing patients to thrombotic phenomena of venous and arterial location, and that in many studies this pathology has been present in patients with negative and positive PCR tests for Covid 19, it requires new studies to confirm that high levels of D-dimer and great involvement of the lung parenchyma are triggers of pulmonary embolism. Imaging tests such as CT angiography are essential to detect patients with pulmonary thromboembolism, as well as its degree, prognosis and treatment., La tromboembolia pulmonar es la obstrucción parcial o completa de una arteria o arterias pulmonares como consecuencia de la migración de un coágulo formado principalmente en miembros pélvicos, aunque ocasionalmente puede provenir de los torácicos, sobre todo en enfermos con catéteres venosos. La metodología utilizada para el presente trabajo de investigación, se enmarca dentro de una revisión bibliográfica de tipo documental, ya que nos vamos a ocupar de temas planteados a nivel teórico como es Embolismo pulmonar en Covid. La técnica para la recolección de datos está constituida por materiales electrónicos, estos últimos como Google Académico, PubMed, Science direct, entre otros, apoyándose para ello en el uso de descriptores en ciencias de la salud o terminología MESH. La información aquí obtenida será revisada para su posterior análisis. A pesar que el Covid causa una respuesta inflamatoria sistémica y daño endotelial que genera un estado de hipercoagulabilidad, con aumento de trombina y disminución de los anticoagulantes naturales, predisponiendo a los pacientes a fenómenos trombóticos de localización venosa y arterial, y que en muchos estudios esta patología ha estado presente en pacientes con pruebas PCR negativas y positivas a Covid 19, requiere nuevos estudios, para confirmar que elevados niveles de dimero D y gran afectación del parénquima pulmonar son detonantes de embolismo pulmonar. Las pruebas de imágenes como la angio TC es fundamental para detectar los pacientes con tromboembolismo pulmonar, así como su grado, pronostico y tratamiento.

Pulmonary thromboembolism is the partial or complete obstruction of a pulmonary artery or arteries as a result of the migration of a clot formed mainly in the pelvic limbs, although it can occasionally come from the thoracic limbs, especially in patients with venous catheters. The methodology used for this research work is part of a documentary-type bibliographic review, since we are going to deal with issues raised at a theoretical level, such as Pulmonary Embolism in Covid. The technique for data collection is made up of electronic materials, the latter such as Google Scholar, PubMed, Science direct, among others, relying for this on the use of descriptors in health sciences or MESH terminology. The information obtained here will be reviewed for further analysis. Despite the fact that Covid causes a systemic inflammatory response and endothelial damage that generates a state of hypercoagulability, with an increase in thrombin and a decrease in natural anticoagulants, predisposing patients to thrombotic phenomena of venous and arterial location, and that in many studies this pathology has been present in patients with negative and positive PCR tests for Covid 19, it requires new studies to confirm that high levels of D-dimer and great involvement of the lung parenchyma are triggers of pulmonary embolism. Imaging tests such as CT angiography are essential to detect patients with pulmonary thromboembolism, as well as its degree, prognosis and treatment., La tromboembolia pulmonar es la obstrucción parcial o completa de una arteria o arterias pulmonares como consecuencia de la migración de un coágulo formado principalmente en miembros pélvicos, aunque ocasionalmente puede provenir de los torácicos, sobre todo en enfermos con catéteres venosos. La metodología utilizada para el presente trabajo de investigación, se enmarca dentro de una revisión bibliográfica de tipo documental, ya que nos vamos a ocupar de temas planteados a nivel teórico como es Embolismo pulmonar en Covid. La técnica para la recolección de datos está constituida por materiales electrónicos, estos últimos como Google Académico, PubMed, Science direct, entre otros, apoyándose para ello en el uso de descriptores en ciencias de la salud o terminología MESH. La información aquí obtenida será revisada para su posterior análisis. A pesar que el Covid causa una respuesta inflamatoria sistémica y daño endotelial que genera un estado de hipercoagulabilidad, con aumento de trombina y disminución de los anticoagulantes naturales, predisponiendo a los pacientes a fenómenos trombóticos de localización venosa y arterial, y que en muchos estudios esta patología ha estado presente en pacientes con pruebas PCR negativas y positivas a Covid 19, requiere nuevos estudios, para confirmar que elevados niveles de dimero D y gran afectación del parénquima pulmonar son detonantes de embolismo pulmonar. Las pruebas de imágenes como la angio TC es fundamental para detectar los pacientes con tromboembolismo pulmonar, así como su grado, pronostico y tratamiento.

Pulmonary thromboembolism is the partial or complete obstruction of a pulmonary artery or arteries as a result of the migration of a clot formed mainly in the pelvic limbs, although it can occasionally come from the thoracic limbs, especially in patients with venous catheters. The methodology used for this research work is part of a documentary-type bibliographic review, since we are going to deal with issues raised at a theoretical level, such as Pulmonary Embolism in Covid. The technique for data collection is made up of electronic materials, the latter such as Google Scholar, PubMed, Science direct, among others, relying for this on the use of descriptors in health sciences or MESH terminology. The information obtained here will be reviewed for further analysis. Despite the fact that Covid causes a systemic inflammatory response and endothelial damage that generates a state of hypercoagulability, with an increase in thrombin and a decrease in natural anticoagulants, predisposing patients to thrombotic phenomena of venous and arterial location, and that in many studies this pathology has been present in patients with negative and positive PCR tests for Covid 19, it requires new studies to confirm that high levels of D-dimer and great involvement of the lung parenchyma are triggers of pulmonary embolism. Imaging tests such as CT angiography are essential to detect patients with pulmonary thromboembolism, as well as its degree, prognosis and treatment., La tromboembolia pulmonar es la obstrucción parcial o completa de una arteria o arterias pulmonares como consecuencia de la migración de un coágulo formado principalmente en miembros pélvicos, aunque ocasionalmente puede provenir de los torácicos, sobre todo en enfermos con catéteres venosos. La metodología utilizada para el presente trabajo de investigación, se enmarca dentro de una revisión bibliográfica de tipo documental, ya que nos vamos a ocupar de temas planteados a nivel teórico como es Embolismo pulmonar en Covid. La técnica para la recolección de datos está constituida por materiales electrónicos, estos últimos como Google Académico, PubMed, Science direct, entre otros, apoyándose para ello en el uso de descriptores en ciencias de la salud o terminología MESH. La información aquí obtenida será revisada para su posterior análisis. A pesar que el Covid causa una respuesta inflamatoria sistémica y daño endotelial que genera un estado de hipercoagulabilidad, con aumento de trombina y disminución de los anticoagulantes naturales, predisponiendo a los pacientes a fenómenos trombóticos de localización venosa y arterial, y que en muchos estudios esta patología ha estado presente en pacientes con pruebas PCR negativas y positivas a Covid 19, requiere nuevos estudios, para confirmar que elevados niveles de dimero D y gran afectación del parénquima pulmonar son detonantes de embolismo pulmonar. Las pruebas de imágenes como la angio TC es fundamental para detectar los pacientes con tromboembolismo pulmonar, así como su grado, pronostico y tratamiento.

Pulmonary thromboembolism is the partial or complete obstruction of a pulmonary artery or arteries as a result of the migration of a clot formed mainly in the pelvic limbs, although it can occasionally come from the thoracic limbs, especially in patients with venous catheters. The methodology used for this research work is part of a documentary-type bibliographic review, since we are going to deal with issues raised at a theoretical level, such as Pulmonary Embolism in Covid. The technique for data collection is made up of electronic materials, the latter such as Google Scholar, PubMed, Science direct, among others, relying for this on the use of descriptors in health sciences or MESH terminology. The information obtained here will be reviewed for further analysis. Despite the fact that Covid causes a systemic inflammatory response and endothelial damage that generates a state of hypercoagulability, with an increase in thrombin and a decrease in natural anticoagulants, predisposing patients to thrombotic phenomena of venous and arterial location, and that in many studies this pathology has been present in patients with negative and positive PCR tests for Covid 19, it requires new studies to confirm that high levels of D-dimer and great involvement of the lung parenchyma are triggers of pulmonary embolism. Imaging tests such as CT angiography are essential to detect patients with pulmonary thromboembolism, as well as its degree, prognosis and treatment., La tromboembolia pulmonar es la obstrucción parcial o completa de una arteria o arterias pulmonares como consecuencia de la migración de un coágulo formado principalmente en miembros pélvicos, aunque ocasionalmente puede provenir de los torácicos, sobre todo en enfermos con catéteres venosos. La metodología utilizada para el presente trabajo de investigación, se enmarca dentro de una revisión bibliográfica de tipo documental, ya que nos vamos a ocupar de temas planteados a nivel teórico como es Embolismo pulmonar en Covid. La técnica para la recolección de datos está constituida por materiales electrónicos, estos últimos como Google Académico, PubMed, Science direct, entre otros, apoyándose para ello en el uso de descriptores en ciencias de la salud o terminología MESH. La información aquí obtenida será revisada para su posterior análisis. A pesar que el Covid causa una respuesta inflamatoria sistémica y daño endotelial que genera un estado de hipercoagulabilidad, con aumento de trombina y disminución de los anticoagulantes naturales, predisponiendo a los pacientes a fenómenos trombóticos de localización venosa y arterial, y que en muchos estudios esta patología ha estado presente en pacientes con pruebas PCR negativas y positivas a Covid 19, requiere nuevos estudios, para confirmar que elevados niveles de dimero D y gran afectación del parénquima pulmonar son detonantes de embolismo pulmonar. Las pruebas de imágenes como la angio TC es fundamental para detectar los pacientes con tromboembolismo pulmonar, así como su grado, pronostico y tratamiento.

Background: Endotheliopathy is suggested as pivotal pathophysiology of sepsis and trauma-associated organ failure, but its role in acute respiratory failure is not yet determined. We investigated if endotheliopathy biomarkers at ICU admission are associated with illness severity and clinical outcomes in patients with acute respiratory failure requiring mechanical ventilation. Methods: We conducted a prospective single-center cohort study including 459 mechanically ventilated adults at ICU admission. Plasma levels of three endotheliopathy biomarkers were measured at ICU admission: Syndecan-1, soluble Thrombomodulin (sTM), and Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1). The primary outcome was the rate of liberation from mechanical ventilation, which is presented together with the rate of the competing risk of death while still on mechanical ventilation. Secondary outcomes were PaO2/FiO2-ratios on admission and on last measurement in patients dying within five days, and 30-day all-cause mortality. The primary outcome and 30-day all-cause mortality were analyzed using Cox regression, controlled for gender, age, chronic obstructive pulmonary disease, septic shock, heart failure, PaO2/FiO2-ratio at admission, respiratory infection, acute kidney injury, and bilirubin. PaO2/FiO2-ratios were analyzed using linear regression, controlled for age, chronic obstructive pulmonary disease, respiratory infection, and shock. Results: Patients with high sTM were liberated from mechanical ventilation at a lower rate (adjusted hazard ratio (HR) 0.71, for an increase from the 25th to the 75th percentile, 95% confidence interval (CI) 0.54–0.93, p = 0.01). Patients with high PECAM-1 were liberated from mechanical ventilation at a lower rate, but only during the first 5 days (adjusted HR 0.72, for an increase from the 25th to the 75th percentile, 95% CI 0.58–0.9, p < 0.01). High levels of Syndecan-1 and PE

Clinically used inhibitors of mammalian target of rapamycin (mTOR) negatively impacts endothelial-dependent vasodilatation (EDD) through unidentified mechanisms. Here we show that either the endothelium-specific deletion of Mtor to inhibit both mTOR complexes, or depletion of Raptor or Rictor to disrupt mTORC1 or mTORC2, causes impaired EDD, accompanied by reduced NO in the serum of mice. Consistently, inhibition of mTOR decreases NO production by human and mouse EC. Specifically, inhibition of mTORC1 suppresses eNOS gene expression, due to impairment in p70S6K-mediated posttranscriptional regulation of the transcription factor KLF2 expression. In contrast to mTORC1 inhibition, a positive-feedback between MAPK (p38 and JNK) activation and Nox2 upregulation contributes to the excessive generation of reactive oxygen species (ROS), which causes eNOS uncoupling and decreased NO bioavailability in mTORC2-inhibited EC. Adeno-associated virus-mediated EC-specific overexpression of KLF2 or suppression of Nox2 restores EDD function in endothelial mTORC1- or mTORC2-inhibited mice.

The cardiovascular system is composed around the central function of the endothelium that lines the inner surfaces of its vessels. In recent years, the existence of a progenitor population within the endothelium has been validated through the study of endothelial colony-forming cells (ECFCs) in human peripheral blood and certain vascular beds. However, our knowledge on endothelial populations in vivo that can give rise to ECFCs in culture has been limited. In this review we report and analyse recent attempts at describing progenitor populations in vivo from murine studies that reflect the self-renewal and stemness capacity observed in ECFCs. We pinpoint seminal discoveries within the field, which have phenotypically defined, and functionally scrutinised these endothelial progenitors. Furthermore, we review recent publications utilising single-cell sequencing technologies to better understand the endothelium in homeostasis and pathology.

Soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) is a cytokine of the TNF superfamily that has a role in injury of different organs including kidney. We hypothesized that in patients with chronic kidney disease (CKD), sTWEAK levels may be related to endothelial dysfunction that usually accompanies the decline of estimated glomerular filtration rate (eGFR). Methods: In 199 patients with different stages of CKD we examined the relationship between sTWEAK plasma levels and CKD stages and the relationship between high sensitivity C reactive protein (hs-CRP), homeostatic model assessment of insulin resistance (HOMA-IR) and sTWEAK concentrations. Results: A gradual decrease in sTWEAK was observed as eGFR decreased. sTWEAK plasma levels were diminished in all stages of CKD and strongly correlated with eGFR. A negative correlation was found between sTWEAK and hs-CRP (p=<0.001) and while a positive correlation was found between sTWEAK and eGFR (p=<0.001). No significant correlation was found between sTWEAK and HOMA-IR. In multivariate regression eGFR, diabetes mellitus and hs-CRP parameters were found to be significant independent variables in decreasing plasma sTWEAK levels. Conclusion: Diminishing of eGFR is accompanied by gradual decreases in sTWEAK plasma levels. Since sTWEAK is strongly and independently correlated with CRP, our study reveals new connections between sTWEAK and endothelial dysfunction in patients with CKD., El inductor débil de apoptosis (sTWEAK) de necrosis tumoral soluble es una citoquina de la superfamilia TNF que tiene un papel en la lesión de diferentes órganos, incluido el riñón. Se planteó la hipótesis de que en pacientes con enfermedad renal crónica (ERC), los niveles de sTWEAK pueden estar relacionados con la disfunción endotelial que generalmente acompaña a la disminución de la tasa de filtración glomerular estimada(TFGe). Material y métodos: En 199 pacientes con diferentes estadios de ERC, se examinó la relación entre los niveles plasmáticos de sTWEAK y los estadios de ERC y la relación entre la proteína reactiva C de alta sensibilidad (hs-CRP), la evaluación del modelo homeostático de resistencia a la insulina (HOMA-IR) y las concentraciones de sTWEAK. Resultados: Se observó una disminución gradual en sTWEAK a medida que disminuyó la TFGe. Los niveles plasmáticos de sTWEAK disminuyeron en todas las etapas de la ERC y se correlacionaron fuertemente con la TFGe. Se encontró una correlación negativa entre sTWEAK y hs-CRP (p=<0,001) y mientras que se encontró una correlación positiva entre sTWEAK y eGFR (p=<0,001). No se encontró correlación significativa entre sTWEAK y HOMA-IR. En la TFGe de regresión multivariada, se encontró que los parámetros de diabetes mellitus y PCR-hs eran variables independientes significativas en la disminución de los niveles plasmáticos de sTWEAK. Conclusión: La disminución de la TFGe se acompaña de disminuciones graduales en los niveles plasmáticos sTWEAK. Dado que sTWEAK se correlaciona fuerte e independientemente con la PCR, nuestro estudio revela nuevas conexiones entre sTWEAK y la disfunción endotelial en pacientes con ERC.