Endothelial-specific knockout of the scramblase TMEM16F impairs in vivo clot formation.

Objective: Loss of function of the phospholipid scramblase (PLS) TMEM16F results in Scott Syndrome, a hereditary bleeding disorder generally attributed to intrinsic platelet dysfunction. The role of TMEM16F in endothelial cells, however, is not well understood. We sought to test the hypothesis that endothelial TMEM16F contributes to hemostasis by measuring bleeding time and venous clotting in endothelial-specific knockout (ECKO) mice.

DISTINCT PATTERNS OF ENDOTHELIAL CELL ACTIVATION PRODUCED BY EXTRACELLULAR HISTONES AND BACTERIAL LIPOPOLYSACCHARIDE.

Objective : Vascular endothelial cells (ECs) sense and respond to both trauma factors (histone proteins) and sepsis signals (bacterial lipopolysaccharide, LPS) with elevations in calcium (Ca 2+ ), but it is not clear if the patterns of activation are similar or different. We hypothesized that within seconds of exposure, histones but not LPS would produce a large EC Ca 2+ response. We also hypothesized that histones would produce different spatio-temporal patterns of Ca 2+ events in veins than in arteries.

Pathogenic soluble tau peptide disrupts endothelial calcium signaling and vasodilation in the brain microvasculature.

The accumulation of the microtubule-associated tau protein in and around blood vessels contributes to brain microvascular dysfunction through mechanisms that are incompletely understood. Delivery of nutrients to active neurons in the brain relies on capillary calcium (Ca) signals to direct blood flow. The initiation and amplification of endothelial cell Ca signals require an intact microtubule cytoskeleton.

Pathogenic soluble tau peptide disrupts endothelial calcium signaling and vasodilation in the brain microvasculature.

The accumulation of the microtubule-associated tau protein in and around blood vessels contributes to brain microvascular dysfunction through mechanisms that are incompletely understood. Delivery of nutrients to active neurons in the brain relies on capillary inositol 1,4,5-triphosphate receptor (IPR)-mediated calcium (Ca) signals to direct blood flow. The initiation and amplification of endothelial cell IPR-mediated Ca signals requires an intact microtubule cytoskeleton.

The Polyanionic Drug Suramin Neutralizes Histones and Prevents Endotheliopathy.

Drugs are needed to protect against the neutrophil-derived histones responsible for endothelial injury in acute inflammatory conditions such as trauma and sepsis. Heparin and other polyanions can neutralize histones but challenges with dosing or side effects such as bleeding limit clinical application. In this study, we demonstrate that suramin, a widely available polyanionic drug, completely neutralizes the toxic effects of individual histones, but not citrullinated histones from neutrophil extracellular traps.

Increased histone-DNA complexes and endothelial-dependent thrombin generation in severe COVID-19.

Coagulopathy in severe COVID-19 is common but poorly understood. The purpose of this study was to determine how SARS-CoV-2 infection impacts histone levels, fibrin structure, and endogenous thrombin potential in the presence and absence of endothelial cells. We studied individuals with SARS-CoV-2 infection and acute respiratory distress syndrome at the time of initiation of mechanical ventilation compared to healthy controls.

Traumatic Brain Injury Impairs Systemic Vascular Function Through Disruption of Inward-Rectifier Potassium Channels.

Trauma can lead to widespread vascular dysfunction, but the underlying mechanisms remain largely unknown. Inward-rectifier potassium channels (Kir2.1) play a critical role in the dynamic regulation of regional perfusion and blood flow.

Impaired capillary-to-arteriolar electrical signaling after traumatic brain injury.

Traumatic brain injury (TBI) acutely impairs dynamic regulation of local cerebral blood flow, but long-term (>72 h) effects on functional hyperemia are unknown. Functional hyperemia depends on capillary endothelial cell inward rectifier potassium channels (Kir2.1) responding to potassium (K) released during neuronal activity to produce a regenerative, hyperpolarizing electrical signal that propagates from capillaries to dilate upstream penetrating arterioles.

Dense and dangerous: The tissue plasminogen activator-resistant fibrinolysis shutdown phenotype is due to abnormal fibrin polymerization.

Background: Both hyperfibrinolysis and fibrinolysis shutdown can occur after severe trauma. The subgroup of trauma patients with fibrinolysis shutdown resistant to tissue plasminogen activator (t-PA)-mediated fibrinolysis have increased mortality. Fibrin polymerization and structure may influence fibrinolysis subgroups in trauma, but fibrin architecture has not been characterized in acutely injured subjects.

Myogenic tone contributes to the regulation of permeability in mesenteric microvessels.

The microvascular endothelium plays a key role in regulating solute permeability in the gut, but the contribution of vascular smooth muscle to barrier function is unknown. We sought to determine the role of vascular smooth muscle and its myogenic tone in the vascular barrier to solutes in mesenteric microvessels. We determined vascular permeability to 4.

Extracellular histones induce calcium signals in the endothelium of resistance-sized mesenteric arteries and cause loss of endothelium-dependent dilation.

Histone proteins are elevated in the circulation after traumatic injury owing to cellular lysis and release from neutrophils. Elevated circulating histones in trauma contribute to coagulopathy and mortality through a mechanism suspected to involve endothelial cell (EC) dysfunction. However, the functional consequences of histone exposure on intact blood vessels are unknown.

Traumatic brain injury impairs sensorimotor function in mice.

Introduction: Understanding the extent to which murine models of traumatic brain injury (TBI) replicate clinically relevant neurologic outcomes is critical for mechanistic and therapeutic studies. We determined sensorimotor outcomes in a mouse model of TBI and validated the use of a standardized neurologic examination scoring system to quantify the extent of injury.

Materials And Methods: We used a lateral fluid percussion injury model of TBI and compared TBI animals to those that underwent sham surgery.

Traumatic Brain Injury Causes Endothelial Dysfunction in the Systemic Microcirculation through Arginase-1-Dependent Uncoupling of Endothelial Nitric Oxide Synthase.

Endothelial dysfunction is a hallmark of many chronic diseases, including diabetes and long-term hypertension. We show that acute traumatic brain injury (TBI) leads to endothelial dysfunction in rat mesenteric arteries. Endothelial-dependent dilation was greatly diminished 24 h after TBI because of impaired nitric oxide (NO) production.

Traumatic brain injury disrupts cerebrovascular tone through endothelial inducible nitric oxide synthase expression and nitric oxide gain of function.

Background: Traumatic brain injury (TBI) has been reported to increase the concentration of nitric oxide (NO) in the brain and can lead to loss of cerebrovascular tone; however, the sources, amounts, and consequences of excess NO on the cerebral vasculature are unknown. Our objective was to elucidate the mechanism of decreased cerebral artery tone after TBI.

Methods And Results: Cerebral arteries were isolated from rats 24 hours after moderate fluid‐percussion TBI.