Rationale: Glycolytic shift is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). It remains unknown how glycolysis increased and contributes to vascular remodeling PAH.Objectives: To determine whether caused by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) PFKFB3-driven induces PAH.Methods: PFKFB3 levels were measured arteries patients animals with PAH. Lactate assessed lungs PAH artery smooth muscle cells (PASMCs). Genetic pharmacologic approaches...

The vascular endothelial growth factor (VEGF) family of cytokines are key drivers blood vessel and remodeling. These ligands act via multiple VEGF receptors (VEGFR) co-receptors such as Neuropilin (NRP) expressed on cells. membrane-associated not solely the cell surface, they move between surface intracellular locations, where can function differently. location receptor alters its ability to ’see’ (access bind to) ligands, which regulates activation; also exposure subcellularly localized...

A monolayer of endothelial cells (ECs) lines the lumen blood vessels and as such provides a semi-selective barrier between interstitial space. Compromise lung EC due to inflammatory or toxic events may results in pulmonary edema, which is cardinal feature acute injury (ALI) its more severe form, respiratory distress syndrome (ARDS). The functions are controlled, at least part, via epigenetic mechanisms mediated by histone deacetylases (HDACs). Zinc-dependent HDACs represent largest group...

Background In endothelial cells (ECs), glycolysis, regulated by PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase, isoform-3), is the major metabolic pathway for ATP generation. preclinical peripheral artery disease models, VEGF

The goal of this study was to investigate the role MLC phosphatase (MLCP) in a LPS model acute lung injury (ALI). We demonstrate that ectopic expression constitutively-active (C/A) MLCP regulatory subunit (MYPT1) attenuates ability increase endothelial (EC) permeability. Down-regulation MYPT1 exacerbates LPS-induced ICAM1 suggesting an anti-inflammatory MLCP. To determine whether contributes ALI vivo, we utilized nanoparticle DNA delivery method specifically target EC. Expression C/A reduced...

Abstract Acute lung injury (ALI) is an acute inflammatory process arises from a wide range of insults. A major cause ALI dysfunction the pulmonary vascular endothelial barrier but mechanisms involved are incompletely understood. The therapeutic potential histone deacetylase (HDAC) inhibitors for treatment cardiovascular and diseases increasingly apparent, by which HDACs regulate function remain to be resolved. We found that specific Class IIa inhibitor, TMP269, significantly attenuated...

Lung vascular endothelial injury in SARS-CoV-2 patients is one of the most important causes morbidity and mortality has been linked to more severe complications including acute respiratory distress syndrome (ARDS) subsequent death due multiorgan failure. We have demonstrated that eight consecutive with SARS-CoV-2, who were not selected for evidence injury, diluted plasma induced intense lung microvascular damage, vitro .

Chronic obstructive pulmonary disease (COPD) is a multisystemic respiratory that associated with progressive airway and vascular remodeling due to the increased proliferation of bronchial smooth muscles cells (BSMCs) arterial muscle (PASMCs) overproduction extracellular matrix (e.g., collagen). Cigarette smoke (CS) several mediators, such as PDGF (platelet-derived growth factor) IL-6, play critical roles in COPD pathogenesis. HDAC6 has been shown be implicated remodeling. However, role...

Pulmonary microvascular endothelial cells (ECs) are integral to the alveoli-capillary barrier of lung. The EC integrity is known be disrupted in severe lung diseases such as acute respiratory distress syndrome (ARDS), pneumonia and pulmonary edema. Mice commonly used model these diseases, dictating an increasingly high demand for murine ECs isolation culture. Despite significant number protocols culture various types cells, remains a challenging procedure. In our manuscript we developed...

Abstract Maintenance of the endothelial cell (EC) barrier is critical to vascular homeostasis and a loss integrity results in increased permeability. While mechanisms that govern EC permeability have been under intense investigation over past several decades, processes regulating preservation/restoration remain poorly understood. Herein we show extracellular purines, adenosine (Ado) 5′‐[γ‐thio]‐triphosphate (ATPγS) can strengthen function human lung microvascular (HLMVEC). This ability...

We have previously shown that Gs‐coupled adenosine receptors (A2a) are primarily involved in adenosine‐induced human pulmonary artery endothelial cell (HPAEC) barrier enhancement. However, the downstream events mediate strengthening of (EC) via signaling largely unknown. In current study, we tested overall hypothesis Rac1 activation and EC enhancement is mediated by Gs‐dependent stimulation cAMP‐dependent Epac1‐mediated cascades. Adenoviral transduction HPAEC with constitutively‐active (C/A)...

BACKGROUND: Endothelial cells (ECs) use glycolysis to produce energy. In preclinical models of peripheral arterial disease, further activation EC was ineffective or deleterious in promoting hypoxia-dependent angiogenesis, whereas pentose phosphate pathway effective. Hexosamine biosynthesis pathway, and are closely linked. Glucosamine directly activates hexosamine pathway. METHODS: Hind-limb ischemia endothelial nitric oxide synthase knockout (eNOS −/− ) BALB/c mice used. (600 μg/g per day)...

Acute lung injury (ALI) is a severe progressive disorder that arises from wide range of causes such as toxins or inflammation, resulting in significant morbidity and mortality. There are no effective therapeutic options apart mechanical ventilation strategies. While the mechanisms govern clinically relevant process increased EC permeability remodeling associated with ALI under intense investigation, our knowledge processes determine barrier enhancement preservation far completion. Recently,...

The vasa vasorum (VV), the microvascular network around large vessels, has been recognized as an important contributor to pathological vascular remodeling in cardiovascular diseases. In bovine and rat models of hypoxic pulmonary hypertension (PH), we have previously shown that chronic hypoxia profoundly increased artery (PA) VV permeability, associated with infiltration inflammatory progenitor cells arterial wall, perivascular inflammation, structural remodeling. Extracellular adenosine was...

Abstract Lipopolysaccharide (LPS), a component of the outer membrane gram-negative bacteria, disrupts alveolar-capillary barrier, triggering pulmonary vascular leak thus inducing acute lung injury (ALI). Extracellular purines, adenosine and ATP, protected against ALI induced by purified LPS. In this study, we investigated whether these purines can impact in more clinically-relevant E.coli (non-sterile LPS) murine model. Mice were inoculated with live E. coli intratracheally (i.t.) or without...

Background: Angiogenesis is the growth of new blood vessels from preexisting vascular structures. Clinical trials using endothelial factor 165a (VEGF165a) for angiogenesis in peripheral arterial disease (PAD) yielded little success. Glycolysis accounts 85% ATP production cells (ECs) and further activated during VEGF165a induced angiogenesis. Our previous research demonstrated interleukin 21 (IL21) promoting PAD models independently pathway. Hypothesis: IL21 utilizes different metabolic...

The vascular endothelial growth factor receptors (VEGFRs) bind to cognate ligands facilitate signaling pathways critical for angiogenesis, the of new capillaries from existing vasculature. Intracellular trafficking regulates availability on cell surface ligands, which regulate activation, and movement activated between intracellular pools, where they can initiate different pathways. Using experimental data computational modeling, we recently demonstrated quantified differential three VEGF...

Abstract The vascular endothelial growth factor (VEGF) family of cytokines are key drivers blood vessel and remodeling. These ligands act via multiple VEGF receptors (VEGFR) co-receptors such as Neuropilin (NRP) expressed on cells. membrane-associated not solely the cell surface, they move between surface intracellular locations, where can function differently. location receptor alters its ability to ‘see’ (access bind to) ligands, which regulates activation; also exposure subcellularly...

Hypothesis: miR-433-3p is a potential therapeutic target to reduce the excess endothelial permeability seen in peripheral skeletal muscle of diabetes. Background: Peripheral arterial disease (PAD) complication systemic atherosclerosis that results from occlusions large arteries leg(s). Though best known as vessel disease, patients with PAD also have microvascular including vascular permeability. Patients diabetes an increased risk develop and more severe symptoms compared nondiabetic...

Acute lung injury (ALI) is devastating disorder with an unacceptably high level of mortality. The pharmacological treatment ALI relies on supportive care and control initiating causes. Therefore, novel therapies are urgently needed to improve clinical outcomes. Endothelial cells (EC) form a semi‐permeable barrier between the interior space blood vessels underlying tissues. characterized by significant pulmonary inflammatory response resulting in protein‐rich edema due loss endothelial...