endothelin-1 and Spinal-Cord-Injuries

Endothelin-1 (ET-1) contributes to the increased peripheral resistance in heart failure and hypertension. Physical inactivity is associated with cardiovascular disease and characterized by increased vascular tone. In this study, we assess the contribution of ET-1 to the increased vascular tone in the extremely deconditioned legs of spinal cord-injured (SCI) individuals before and after exercise training.. In 8 controls and 8 SCI individuals, bilateral thigh blood flow was measured by plethysmography before and during the administration of an ET(A)/ET(B)-receptor blocker into the femoral artery. In SCI, this procedure was repeated after 6 weeks of electro-stimulated training. In a subset of SCI (n=4), selective ET(A)-receptor blockade was performed to determine the role of the ET(A)-receptors. In controls, dual ET-receptor blockade increased leg blood flow at the infused side (10%, P<0.05), indicating a small contribution of ET-1 to leg vascular tone. In SCI, baseline blood flow was lower compared with controls (P=0.05). In SCI, dual ET-receptor blockade increased blood flow (41%, P<0.001). This vasodilator response was significantly larger in SCI compared with controls (P<0.001). The response to selective ET(A)-receptor blockade was similar to the effect of dual blockade. Electro-stimulated training normalized baseline blood flow in SCI and reduced the response to dual ET-receptor blockade in the infused leg (29%, P=0.04).. ET-1 mediates the increased vascular tone of extremely inactive legs of SCI individuals by increased activation of ET(A)-receptors. Physical training reverses the ET-1-pathway, which normalizes basal leg vascular tone.

Topics: Adult; Antihypertensive Agents; Case-Control Studies; Electric Stimulation Therapy; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Exercise; Female; Femoral Artery; Humans; Male; Middle Aged; Muscle, Skeletal; Muscular Atrophy; Oligopeptides; Peptides, Cyclic; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Regional Blood Flow; Signal Transduction; Spinal Cord Injuries; Vasodilation

Spinal cord injury could cause irreversible neurological dysfunction by destroying the blood-spinal cord barrier (BSCB) and allowing blood cells like neutrophils and macrophages to infiltrate the spinal cord. Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) found in the human umbilical cord have emerged as a potential therapeutic alternative to cell-based treatments. This study aimed to investigate the mechanism underlying the alterations in the BSCB permeability by human umbilical cord MSC-derived sEVs (hUC-MSCs-sEVs) after SCI. First, we used hUC-MSCs-sEVs to treat SCI rat models, demonstrating their ability to inhibit BSCB permeability damage, improve neurological repair, and reduce SCI-induced upregulation of prepro-endothelin-1 (prepro-ET-1) mRNA and endothelin-1 (ET-1) peptide expression. Subsequently, we confirmed that hUC-MSCs-sEVs could alleviate cell junction destruction and downregulate MMP-2 and MMP-9 expression after SCI, contributing to BSCB repair through ET-1 inhibition. Finally, we established an

Topics: Animals; Down-Regulation; Endothelial Cells; Endothelin-1; Extracellular Vesicles; Humans; Mesenchymal Stem Cells; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Umbilical Cord

The aim of this study was to investigate the effect of microRNA-214-5p (miR-214-5p) on spinal cord injury (SCI) and to explore the mechanism of action in pathophysiological relevance.. The model of SCI was successfully established in rats aged 6-8 weeks. The levels of the locomotor function recovery in rats of the miR-379-5p group and SCI group were detected one month later by Basso-Beattie-Bresnahan (BBB) locomotor rating scale. Biochemical indexes were measured by Western blotting and real time-PCR, respectively. In addition, rat astrocytes were cultured to verify the effect of miR-379-5p on activated astrocytes in vitro.. Compared with the SCI group, the rats in the miR-379-5p group showed prominent improvement in the locomotor function in vivo. MiR-379-5p attenuated the activation of astrocytes and significantly suppressed the expressions of the nerve growth inhibitors. Furthermore, the down-regulation of endothelin-1 (ET-1) ameliorated the spinal cord ischemia, thereby reducing apoptosis and oxidative stress. Compared with the pentylenetetrazol (PTZ) group, ET-1 and chondroitin sulfate poly-glycoprotein (CSPG) in miR-379-5p group decreased significantly in the astrocytes transfected with miR-214-5p in vitro.. MiR-379-5p retarded the neurofilament regeneration block effect by inhibiting endothelin 1 and the expression of the astrocytes after SCI. Furthermore, it might relieve nerve structure destruction, resist oxidative stress, and inhibit apoptosis, eventually promoting functional recovery.

Topics: Animals; Astrocytes; Disease Models, Animal; Endothelin-1; Female; Locomotion; MicroRNAs; Oxidative Stress; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord Injuries

Recent studies have found increased markers of endothelial activation in men with chronic spinal cord injury. This study was conducted to determine the effects of arm-cranking exercise on endothelial dysfunction in male adults with chronic SCI.. A prospective randomized study of 17 sedentary adult males with chronic SCI at or under T5 level. Nine performed a supervised exercise program at a moderate intensity (arm-cranking: 12 weeks, 3 sessions/week). Plasma levels of endothelin-1, soluble intercellular adhesion molecule type 1 (sICAM-1), and soluble vascular adhesion molecule type 1 (sVCAM-1) were assessed by ELISA. Outcome measurements also included physical fitness and total body fat mass percentage.. We observed both in the randomized and in the before-after studies a significant reduction of the levels of endothelin-1 and sICAM-1. Furthermore, significant improvements of both physical fitness and body composition were also found.. Arm-cranking exercise improved endothelial dysfunction in adult males with chronic SCI. Long-term studies are still required to determine whether the correction of endothelial dysfunction improves the clinical outcomes of adults with chronic SCI.

Topics: Adiposity; Adult; Arm; Biomarkers; Body Composition; Endothelin-1; Endothelium, Vascular; Exercise Therapy; Humans; Intercellular Adhesion Molecule-1; Male; Prospective Studies; Sedentary Behavior; Spinal Cord Injuries; Treatment Outcome; Vascular Cell Adhesion Molecule-1

Plasma endothelin-1 (ET-1) levels are elevated in spinal cord injury (SCI), and ET-1 may be involved in the pathophysiology of this condition. However, its effects on contractile function of the heart of SCI rats are still unknown. To define more clearly the possible role of ET-1 following SCI, we investigated the effect of ET-1 on the contraction, calcium transients and L-type calcium current (I(Ca,L)) in the cardiomyocytes of control and SCI rats. Sixteen Sprague-Dawley male rats aged 80-100 days and weighing 250-350 g were randomized into control and SCI groups. Fourteen days following compression injury to the spinal cord, effects of ET-1 on the contraction, calcium transients and I(Ca,L) were studied in the cardiomyocytes of control and SCI rats by the technique of simultaneous measurement of intracellular Ca(2+) and contraction and by whole-cell configuration of the patch-clamp technique. In myocytes from control rats, ET-1 significantly increased contraction, the magnitude of Ca(2+) transients and the peak amplitude of I(Ca,L). However, ET-1 had little effect on the amplitude of contraction, calcium transients and I(Ca,L). in myocytes from SCI rats. These results suggest that the positive inotropic effects of ET-1 on control myocardial contraction may be altered in pathological states such as SCI.

Topics: Animals; Calcium; Calcium Channels, L-Type; Dose-Response Relationship, Drug; Endothelin-1; Male; Myocardial Contraction; Myocytes, Cardiac; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries

Accelerated atherogenesis is often seen in individuals with chronic spinal cord injury (SCI). However, the mechanisms contributing to this phenomenon remain unclear. This study aimed to evaluate whether SCI per se is associated with a low-grade chronic inflammatory state and endothelial activation, both of which are well-documented prerequisites for atherogenesis.. Serum levels of markers of inflammation (C-reactive protein [CRP], interleukin-6, and soluble CD40 ligand) and endothelial activation (endothelin-1, soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1 [sVCAM-1]) were measured in SCI patients with CRP levels < 10 mg/L and with no evidence of active infection. Sixty-two men with traumatic neurologically complete SCI (20 tetraplegics and 42 paraplegics) and 29 age-matched male controls were enrolled.. Compared with able-bodied controls, subjects with SCI had a significantly lower body mass index (BMI) (-7%) and significantly lower serum levels of albumin (-10%), creatinine (-20%), low-density lipoprotein cholesterol (-10%), and high-density lipoprotein (HDL) cholesterol (-25%), and showed a trend toward higher fasting insulin levels. Irrespective of injury level and duration, subjects with SCI had significantly higher serum levels, compared to able-bodied controls, of CRP (mean, 4.0 +/- 2.7 mg/L vs. 1.4 +/- 1.1 mg/L), interleukin-6 (median, 2.5 pg/mL vs. 0.4 pg/mL; range, 1.5-3.6 pg/mL vs. 0.2-0.5 pg/mL), endothelin-1 (mean, 1.3 +/- 0.4 pg/mL vs. 0.9 +/- 0.3 pg/mL), and sVCAM-1 (mean, 1170 +/- 318 ng/mL vs. 542 +/- 318 ng/mL). The serum levels of all four factors correlated negatively with levels of serum albumin, creatinine and HDL cholesterol, but not with BMI or fasting insulin levels. In multivariate analyses, SCI was the only factor that was independently associated with increased serum levels of CRP, interleukin-6, endothelin-1 and sVCAM-1 after adjustment for confounding factors such as serum albumin and creatinine levels and parameters of dyslipidemia and insulin resistance.. In this study, we have, for the first time, demonstrated that SCI per se is associated with a low-grade chronic inflammatory state and endothelial activation, which may partly explain the increased atherogenic risk in patients with long-standing SCI.

Topics: Adolescent; Adult; Biomarkers; C-Reactive Protein; Case-Control Studies; Endothelin-1; Humans; Interleukin-6; Male; Middle Aged; Spinal Cord Injuries; Vascular Cell Adhesion Molecule-1

To study the effects of high level spinal cord injury (SCI) on rat heart, and investigate the role of endothelin-1 (ET-1) in the harmful effects on heart after SCI.. Forty-eight male SD rats were randomly divided into six groups of 8 animals each: control group; 4-hour group: 4 th hour after injury to spinal cord at cervical 7 level; 12-hour group: 12 th hour after injury to 7 spinal cord at C7 level; 24-hour group with same injury; 48-hour group and 72-hour group, all with same injury. Mean arterial pressure (MAP), heart rate (HR), left ventricle systolic pressure (LVSP), and left ventricular maximum velocities of contraction (+/-dp/dt max) were recorded in each group. Lactate dehydrogenase (LDH), creatine kinase (CK), MB isoenzyme of creatine kinase (CK-MB) and ET-1 contents in the myocardium. were also measured. Specimens of the myocardium were harvested for ultrastructure examination with transmission electron microscopy.. Hemodynamics variables including HR, MAP, LVSP and+/-dp/dtmax were significantly decreased in all the injury groups compared with that of control group (P<0.05 or P<0.01). These variables in 12-hour group showed lowest values among all the groups (all P<0.01). But the values of cardiac enzymes were much higher in five injury groups compared with that of control group (P<0.05 or P<0.01). ET-1 contents in serum and cardiac tissue raised markedly after the injury was inflicted to the animals (P<0.05), reaching peak at 12 hours (P<0.01). Ultrastructural examination of the myocardial tissue demonstrated that there were mild dissolution of myocardial fibrils and vacuolation of mitochondria at 12 hours after injury.. High level SCI could induce myocardial injuries and an excessive production of ET-1 in circulation and myocardial tissue might play a role in myocardial damage after injury of the spinal cord at a high level.

Topics: Animals; Disease Models, Animal; Endothelin-1; Heart; Male; Myocardium; Random Allocation; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries

We developed a rat spinal cord injury model and investigated whether endogenous endothelin (ET)-1 plays a role in astrocytic growth after injury. Immunohistochemical study showed that the number of immature astrocytes (ACs) exhibiting strong reactivity to the monoclonal antibody, RC1, markedly increased 24 h after the injury. Injection of a potent nonselective ET receptor antagonist, SB209670, into the lesion sites significantly inhibited the appearance of RC1-positive cells 24 h after the injury. In conjunction with this result, the increase in immunostaining density of 5-bromo-2'-deoxyuridine in the spinal cord 24 h after the injury was inhibited by the injection of SB209670. The tissue content of ET-1-LI was significantly increased 12 and 24 h after the injury. These results suggest that endogenous ET-1 is involved in astrocytic growth after spinal cord injury.

Topics: Animals; Astrocytes; Cell Division; Endothelin-1; Immunohistochemistry; Rats; Rats, Wistar; Spinal Cord Injuries