Adequate post-ischemic reperfusion of the mouse brain requires endothelial NFAT5.

Severity and outcome of strokes following cerebral hypoperfusion are significantly influenced by stress responses of the blood vessels. In this context, brain endothelial cells (BEC) regulate inflammation, angiogenesis and the vascular resistance to rapidly restore perfusion. Despite the relevance of these responses for infarct volume and tissue recovery, their transcriptional control in BEC is not well characterized.

Antibodies and complement are key drivers of thrombosis.

Venous thromboembolism (VTE) is a common, deadly disease with an increasing incidence despite preventive efforts. Clinical observations have associated elevated antibody concentrations or antibody-based therapies with thrombotic events. However, how antibodies contribute to thrombosis is unknown.

Nuclear factor of activated T-cells 5 is indispensable for a balanced adaptive transcriptional response of lung endothelial cells to hypoxia.

Aims: Chronic hypoxia causes detrimental structural alterations in the lung, which may cause pulmonary hypertension and are partially mediated by the endothelium. While its relevance for the development of hypoxia-associated lung diseases is well known, determinants controlling the initial adaptation of the lung endothelium to hypoxia remain largely unexplored.

Methods And Results: We revealed that hypoxia activates the transcription factor nuclear factor of activated T-cells 5 (NFAT5) and studied its regulatory function in murine lung endothelial cells (MLECs).

Endothelial Heterogeneity in the Response to Autophagy Drives Small Vessel Muscularization in Pulmonary Hypertension.

Background: Endothelial cell (EC) apoptosis and proliferation of apoptosis-resistant cells is a hallmark of pulmonary hypertension (PH). Yet, why some ECs die and others proliferate and how this contributes to vascular remodeling is unclear. We hypothesized that this differential response may: (1) relate to different EC subsets, namely pulmonary artery (PAECs) versus microvascular ECs (MVECs); (2) be attributable to autophagic activation in both EC subtypes; and (3) cause replacement of MVECs by PAECs with subsequent distal vessel muscularization.

Activation of the hypoxia-inducible factor pathway protects against acute ischemic stroke by reprogramming central carbon metabolism.

Cell metabolism reprogramming to sustain energy production, while reducing oxygen and energy consuming processes is crucially important for the adaptation to hypoxia/ischemia. Adaptive metabolic rewiring is controlled by hypoxia-inducible factors (HIFs). Accumulating experimental evidence indicates that timely activation of HIF in brain-resident cells improves the outcome from acute ischemic stroke.

Endothelial cells drive organ fibrosis in mice by inducing expression of the transcription factor SOX9.

Fibrosis is a hallmark of chronic disease. Although fibroblasts are involved, it is unclear to what extent endothelial cells also might contribute. We detected increased expression of the transcription factor in endothelial cells in several different mouse fibrosis models.

Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia.

Cachexia is a major cause of morbidity and mortality in individuals with cancer and is characterized by weight loss due to adipose and muscle tissue wasting. Hallmarks of white adipose tissue (WAT) remodeling, which often precedes weight loss, are impaired lipid storage, inflammation and eventually fibrosis. Tissue wasting occurs in response to tumor-secreted factors.

Tracing G-Protein-Mediated Contraction and Relaxation in Vascular Smooth Muscle Cell Spheroids.

Analyses of G-protein-mediated contraction and relaxation of vascular smooth muscle cells (VSMCs) are usually hampered by a rigid growth surface and culture conditions promoting cell proliferation and a less contractile phenotype. Our studies indicated that mouse aortic VSMCs cultured in three-dimensional spheroids acquire a quiescent contractile status while decreasing the baseline G-protein-dependent inositolphosphate formation and increasing the expression of endothelin receptor type A (). Endothelin-1 (ET-1) promoted inositolphosphate formation in VSMC spheroids, but not in VSMCs cultured under standard conditions.

Adeno-Associated Virus-Mediated Gene Transfer of Inducible Nitric Oxide Synthase to an Animal Model of Pulmonary Hypertension.

Pulmonary hypertension (PH) is characterized by progressive obstruction of pulmonary arteries owing to inflammatory processes, cellular proliferation, and extracellular matrix deposition and vasoconstriction. As treatment options are limited, we studied gene transfer of an inducible nitric oxide synthase (iNOS) using adeno-associated virus (AAV) vectors specifically targeted at endothelial cells of pulmonary vessels in a murine model of PH. Adult mice were intravenously injected with AAV vectors expressing iNOS.

NFAT5/TonEBP Limits Pulmonary Vascular Resistance in the Hypoxic Lung by Controlling Mitochondrial Reactive Oxygen Species Generation in Arterial Smooth Muscle Cells.

Chronic hypoxia increases the resistance of pulmonary arteries by stimulating their contraction and augmenting their coverage by smooth muscle cells (SMCs). While these responses require adjustment of the vascular SMC transcriptome, regulatory elements are not well defined in this context. Here, we explored the functional role of the transcription factor nuclear factor of activated T-cells 5 (NFAT5/TonEBP) in the hypoxic lung.

Loss of Nfat5 promotes lipid accumulation in vascular smooth muscle cells.

The nuclear factor of activated T-cells 5 (NFAT5) is a transcriptional regulator of macrophage activation and T-cell development, which controls stabilizing responses of cells to hypertonic and biomechanical stress. In this study, we detected NFAT5 in the media layer of arteries adjacent to human arteriosclerotic plaques and analyzed its role in vascular smooth muscle cells (VSMCs) known to contribute to arteriosclerosis through the uptake of lipids and transformation into foam cells. Exposure of both human and mouse VSMCs to cholesterol stimulated the nuclear translocation of NFAT5 and increased the expression of the ATP-binding cassette transporter Abca1, required to regulate cholesterol efflux from cells.

RGS5 Attenuates Baseline Activity of ERK1/2 and Promotes Growth Arrest of Vascular Smooth Muscle Cells.

The regulator of G-protein signaling 5 (RGS5) acts as an inhibitor of Gα and Gα activity in vascular smooth muscle cells (VSMCs), which regulate arterial tone and blood pressure. While RGS5 has been described as a crucial determinant regulating the VSMC responses during various vascular remodeling processes, its regulatory features in resting VSMCs and its impact on their phenotype are still under debate and were subject of this study. While shows a variable expression in mouse arteries, neither global nor SMC-specific genetic ablation of affected the baseline blood pressure yet elevated the phosphorylation level of the MAP kinase ERK1/2.

Associations Between Children's Physical Activity, Pain and Injuries.

Our aim in this study was to investigate the relationships between physical activity (PA), pain, and injury among children. Secondarily, we examined whether these relationships differed between children with normal versus excessive weight or obesity. This was a cross-sectional study of 102 children (57 girls) aged 8-12 years old.

Trigger-Specific Remodeling of K2 Potassium Channels in Models of Atrial Fibrillation.

Aim: Effective antiarrhythmic treatment of atrial fibrillation (AF) constitutes a major challenge, in particular, when concomitant heart failure (HF) is present. HF-associated atrial arrhythmogenesis is distinctly characterized by prolonged atrial refractoriness. Small-conductance, calcium-activated K (K, SK, ) channels contribute to cardiac action potential repolarization and are implicated in AF susceptibility and therapy.

Endothelial cells control vascular smooth muscle cell cholesterol levels by regulating 24-dehydrocholesterol reductase expression.

Communication of vascular cells is essential for the control of organotypic functions of blood vessels. In this context, vascular endothelial cells (EC) act as potent regulators of vascular smooth muscle cell (VSMC) functions such as contraction and relaxation. However, the impact of ECs on the gene expression pattern of VSMCs is largely unknown.

Progressive resistance training for adolescents with cerebral palsy: the STAR randomized controlled trial.

Aim: To evaluate the effect of progressive resistance training of the ankle plantarflexors on gait efficiency, activity, and participation in adolescents with cerebral palsy (CP).

Method: Sixty-four adolescents (10-19y; 27 females, 37 males; Gross Motor Function Classification System [GMFCS] levels I-III) were randomized to 30 sessions of resistance training (10 supervised and 20 unsupervised home sessions) over 10 weeks or usual care. The primary outcome was gait efficiency indicated by net nondimensional oxygen cost (NNcost).

Optimal mass of the arm segments in throwing: A two-dimensional computer simulation study.

Producing a high release speed is important in throwing sports such as baseball and the javelin throw. Athletes in throwing sports might be able to achieve a greater throwing speed by improving the effectiveness of the kinetic chain. In this study a two-dimensional computer simulation model of overarm throwing was used to examine the effect of changes in forearm mass and upper arm mass on the release speed of a lightweight (58 g) projectile.

Validity of the International Physical Activity Questionnaire Short Form (IPAQ-SF) as a measure of physical activity (PA) in young people with cerebral palsy: A cross-sectional study.

Objectives: The aim of this study was to examine the validity of the International Physical Activity Questionnaire Short Form (IPAQ-SF) as a measure of physical activity (PA) in young people with cerebral palsy (CP).

Design: Cross-sectional.

Setting: Participants were recruited through 8 National Health Service (NHS) trusts, one school, one university and through organisations that provide services for people with disabilities in England.

Assembly of vascular smooth muscle cells in 3D aggregates provokes cellular quiescence.

Three-dimensional (3D) cell culture conditions are often used to promote the differentiation of human cells as a prerequisite for the study of organotypic functions and environment-specific cellular responses. Here, we assessed the molecular and functional phenotype of vascular smooth muscle cells (VSMCs) cultured as 3D multilayered aggregates. Microarray studies revealed that these conditions decrease the expression of genes associated with cell cycle control and DNA replication and cease proliferation of VSMCs.

Risk and protective factors for post-thrombotic syndrome after deep venous thrombosis.

Objective: The most frequent complication of deep venous thrombosis (DVT) is post-thrombotic syndrome (PTS). We recently showed inhibition of varicose vein development by atorvastatin and rosuvastatin. The aim of this study was to test the influence of lipid-lowering therapy with statins on PTS development.

Loss of the serine protease HTRA1 impairs smooth muscle cells maturation.

Vascular smooth muscle cell (VSMC) dysfunction is a hallmark of small vessel disease, a common cause of stroke and dementia. Two of the most frequently mutated genes in familial small vessel disease are HTRA1 and NOTCH3. The protease HTRA1 cleaves the NOTCH3 ligand JAG1 implying a mechanistic link between HTRA1 and Notch signaling.

Predictors of Walking Efficiency in Children With Cerebral Palsy: Lower-Body Joint Angles, Moments, and Power.

Background: People with cerebral palsy (CP) experience increased muscle stiffness, muscle weakness, and reduced joint range of motion. This can lead to an abnormal pattern of gait, which can increase the energy cost of walking and contribute to reduced participation in physical activity.

Objective: The aim of the study was to examine associations between lower-body joint angles, moments, power, and walking efficiency in adolescents with CP.

Biomechanical evaluation of walking and cycling in children.

Physical activity in children is important as it leads to healthy growth due to physiological benefits. However, a physiological benefit can be partially negated by excessive or unphysiological loads within the joints. To gain an initial understanding into this, the present study sought to compare joint loading between walking and cycling in children.

EphB2-dependent signaling promotes neuronal excitotoxicity and inflammation in the acute phase of ischemic stroke.

Local cerebral hypoperfusion causes ischemic stroke while driving multiple cell-specific responses including inflammation, glutamate-induced neurotoxicity mediated via NMDAR, edema formation and angiogenesis. Despite the relevance of these pathophysiological mechanisms for disease progression and outcome, molecular determinants controlling the onset of these processes are only partially understood. In this context, our study intended to investigate the functional role of EphB2, a receptor tyrosine kinase that is crucial for synapse function and binds to membrane-associated ephrin-B ligands.

[Drug-Based Therapy of Varicose Veins from the Perspective of Experimental Models].

Drug-Based Therapy of Varicose Veins from the Perspective of Experimental Models Abstract. Varicose remodeling of the venous wall primarily occurs in the lower extremities and is often associated with venous insufficiency. Although a large part of the western population shows various degrees of varicosis, little is known about the mechanisms driving their formation.