Endothelial Dysfunction, Spinal Cord Injuries
Conditions
Keywords
spinal cord injury, endothelium-dependent vasodilation, extracellular vesicles, microvesicles
Brief summary
This study plans to learn how endothelial cells, single cell lining of blood vessels may be dysfunctional after a spinal cord injury. Endothelial dysfunction will be measured by the capacity of blood vessels to vasodilate (increase in size) and alter blood flow is lower in adults with a spinal cord injury in comparison to adults without a spinal cord injury. The mechanisms which may alter this function may be critical in reducing the risk of heart attacks and strokes in people with spinal cord injuries.
Detailed description
Vascular endothelial dysfunction is prevalent after spinal cord injury (SCI) which predispose individuals with SCI to accelerated, atherosclerotic cardiovascular disease (ASCVD) and future myocardial infarctions and ischemic strokes. The central objective of this study is to determine whether adults with SCI exhibit impaired endothelial function. Specifically, if endothelium-dependent vasodilation is impaired and if endothelial cell derived microvesicles (EMVs) are elevated and dysfunctional in adults with paraplegia. Endothelium-dependent vasodilation will be assessed by pharmacologically manipulating endothelial vasodilator function in live conscious humans with SCI and determining the role of circulating EMVs as both a systemic biomarker and mediator of endothelial dysfunction.
Interventions
A catheter is placed in the brachial artery of the non-dominant arm, and small doses of vasoactive drugs \[acetylcholine (Ach), isoproterenol (ISO), sodium nitroprusside (SNP)\] are infused. Forearm blood flow (FBF) is measured using venous occlusion plethysmography. The purpose of this procedure is to assess endothelium-dependent and independent vasodilation by stimulating different vascular pathways. The Ach infusion is to test muscarinic receptor, nitro oxide (NO) dependent, endothelium-dependent vasodilation. ISO infusion is to evaluate β-adrenergic, NO-dependent endothelium-dependent vasodilation. SNP infusion is to assess endothelium-independent vasodilation.
PROCEDUREIntra-arterial Vitamin C Infusion
Vitamin C, a potent antioxidant, will be infused into the arm and forearm blood flow (FBF) will be re-evaluated to determine whether oxidative stress contributes to endothelial dysfunction.
PROCEDUREBlood Sampling
Blood will be sampled from the antecubital vein (\ 50 mL) for biomarker analysis. This is to assess circulating biochemical and molecular indicators of vascular health and inflammation including levels of endothelial cell derived microvesicles (EMVs)
Sponsors
University of Colorado, Boulder
Denver Health and Hospital Authority
Craig Hospital
Study design
Observational model
CASE_CONTROL
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
SCI Inclusion Criteria * Over age 18 years * Chronic (\>12 months) SCI * Motor complete (AIS A/B) SCI * Paraplegia (neurological level of injury \[NLI\] at T2 or below) Non-injured Inclusion Criteria • Over age 18 years
Exclusion criteria
(Both SCI and Non-injured) * Overt chronic diseases as assessed by: a) clinically documented medical history; b) physical examination; c) blood pressure and ECG at rest; and d) complete blood chemistries and hematological evaluation. * Active infection * Recent (\< 3 months) surgery * Current smoking history (within past 12 months) * Report more than low-risk alcohol consumption * History of drug abuse * Currently taking cardiovascular (statins, beta-blockers) therapeutics and/or other medications that could influence the outcome measures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Endothelial cell-derived microvesicles effects of human coronary artery endothelial cells reactive oxygen species and antioxidant capacity | Baseline | Endothelial cell-derived microvesicles will be sorted and collected by fluorescence-activated cell sorting (FACS) flow cytometry. The endothelial cell-derived microvesicles will be co-cultured with human coronary artery endothelial cells. Super oxide dismutase and catalase expression will be measured by intracellular protein expression quantification of whole cell lysates by capillary electrophoresis immunoassays. Intracellular oxidative stress will be assessed by ROS-Glo H2O2 assay. |
| Endothelium-dependent vasodilation | Measured at baseline and immediately after each vasoactive dose for 3-5 minutes. | Total forearm blood flow with be measured by strain gauge venous plethysmography under baseline conditions and under pharmacological manipulation with acetylcholine and isoproterenol at increasing concentrations. |
| Endothelium-independent vasodilation | Measured at baseline (without sodium nitroprusside) and immediately after each sodium nitroprusside dose for 3-5 minutes. | Total forearm blood flow with be measured by strain gauge venous plethysmography under baseline conditions and under pharmacological manipulation with sodium nitroprusside at increasing concentrations (1, 2, 4ug/ml). |
| Endothelial cell-derived microvesicles concentration | Baseline | Endothelial cell-derived microvesicles will be collected from venous blood samples and counted used flow cytometry to determine a circulating concentration. |
| Endothelial cell-derived microvesicles effects of human coronary artery endothelial cells nitric oxide bioavailability | Baseline | Endothelial cell-derived microvesicles will be sorted and collected by fluorescence-activated cell sorting (FACS) flow cytometry. The endothelial cell-derived microvesicles will be co-cultured with human coronary artery endothelial cells. Endothelial Nitric Oxide Synthase and phosphorylation sites of interest will be measured by intracellular protein expression quantification of whole cell lysates by capillary electrophoresis immunoassays. Nitric oxide production will be assessed by total nitric oxide and nitrate/nitrite parameter assays. |
Countries
United States
Contacts
Primary ContactGenevieve Madera, BS
Backup ContactClare Morey, SLP-CCC
Outcome results
None listed