Skip to main content
NCBI home page
Topics in Spinal Cord Injury Rehabilitation logoLink to Topics in Spinal Cord Injury Rehabilitation
. 2023 Apr 3;29(2):34–42. doi: 10.46292/sci22-00032

Differential Expression of Vascular-Related MicroRNA in Circulating Endothelial Microvesicles in Adults With Spinal Cord Injury: A Pilot Study

Andrew J Park 1,2,✉, Hannah K Fandl 3, Vinicius P Garcia 3, Geoff B Coombs 4, Noah M DeSouza 3,5, Jared J Greiner 3, Otto F Barak 6,7, Tanja Mijacika 7, Zeljko Dujic 7, Philip N Ainslie 5, Christopher A DeSouza 3
PMCID: PMC10208256  PMID: 37235195

Abstract

Background

Spinal cord injury (SCI) is associated with an increased risk and prevalence of cardiopulmonary and cerebrovascular disease-related morbidity and mortality. The factors that initiate, promote, and accelerate vascular diseases and events in SCI are poorly understood. Clinical interest in circulating endothelial cell-derived microvesicles (EMVs) and their microRNA (miRNA) cargo has intensified due to their involvement in endothelial dysfunction, atherosclerosis, and cerebrovascular events.

Objectives

The aim of this study was to determine whether a subset of vascular-related miRNAs is differentially expressed in EMVs isolated from adults with SCI.

Methods

We assessed eight adults with tetraplegia (7 male/1 female; age: 46±4 years; time since injury: 26±5 years) and eight uninjured (6 male/2 female; age: 39±3 years). Circulating EMVs were isolated, enumerated, and collected from plasma by flow cytometry. The expression of vascular-related miRNAs in EMVs was assessed by RT-PCR.

Results

Circulating EMV levels were significantly higher (~130%) in adults with SCI compared with uninjured adults. The expression profile of miRNAs in EMVs from adults with SCI were significantly different than uninjured adults and were pathologic in nature. Expression of miR-126, miR-132, and miR-Let-7a were lower (~100–150%; p < .05), whereas miR-30a, miR-145, miR-155, and miR-216 were higher (~125–450%; p < .05) in EMVs from adults with SCI.

Conclusion

This study is the first examination of EMV miRNA cargo in adults with SCI. The cargo signature of vascular-related miRNAs studied reflects a pathogenic EMV phenotype prone to induce inflammation, atherosclerosis, and vascular dysfunction. EMVs and their miRNA cargo represent a novel biomarker of vascular risk and a potential target for intervention to alleviate vascular-related disease after SCI.

Keywords: cardiovascular disease, endothelial microvesicles, microRNA, spinal cord injury

Introduction

Spinal cord injury (SCI) is associated with an increased risk and prevalence of cardiovascular and cerebrovascular disease-related morbidity and mortality.1,2 The increased incidence of vascular disease in adults with chronic SCI does not appear to be solely due to worsening of traditional risk factors, such as increased adiposity, blood pressure instability, dyslipidemia, and insulin resistance; it also involves ill-defined factors that appear to be SCI specific.3 In fact, after controlling for such factors, individuals with SCI demonstrate presymptomatic vascular disease in carotid and coronary arteries, which are associated with vascular events including ischemic stroke and myocardial infarction.4–7

Initially considered inert cellular debris, clinical interest in circulating extracellular vesicles, specifically endothelial cell-derived microvesicles (EMVs), has intensified due to their role in the development of endothelial dysfunction and atherosclerosis.8–12 EMVs are known to contain microRNA (miRNA), and the expression signature of their miRNA cargo is considered a key factor in dictating the cellular, and potential pathologic, effects of EMVs.13,14 Indeed, lower expression of miR-126 in circulating EMVs is associated with greater formation of atherosclerotic plaque in a murine model as well as higher incidence of vascular disease in adult humans.15,16 Circulating EMVs have been shown to be elevated in individuals living with SCI and may contribute to the increased risk of vascular disease and events in individuals with an SCI.17 However, it is not known whether SCI is associated with differential expression of EMV-miRNA cargo.

Accordingly, the experimental aim of this study was to determine whether a subset of specific vascular-related miRNAs, known to be associated with vascular risk and disease, are differentially expressed in EMVs isolated from adults with SCI. Specifically, we tested the hypothesis that the expression of miR-30a, miR-126, miR-132, miR-145, miR-155, miR-216, and miR-Let-7a would be unfavorable in EMVs from adults with SCI compared with uninjured adults.

Methods

Participants

Sixteen young and middle-aged adults (36–50 years) were studied: eight uninjured (6 male/2 female) and eight with chronic tetraplegia (7 male/1 female; average time since injury: 26±5 years). Injury characteristics per International Standards for Neurological Classification of Spinal Cord Injury included neurological level of injury of C3, n = 1; C5, n = 4; and C6, n = 3. Based on American Spinal Injury Association Impairment Scale (AIS), adults with SCI included A, n = 1; B, n = 4; and C, n = 3. All participants were free of overt cardiovascular and metabolic disease assessed by medical history, resting electrocardiograms, and fasting blood chemistry. Prior to participation in the study, the study risks and benefits were explained and written informed consent was completed and obtained in compliance with the Ethics Committee of the School of Medicine at the University of Split, Croatia. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. The present study originated from a larger investigation on the influence of SCI on cardiovascular function17; although a small portion of the same volunteers are included, the miRNA data presented herein address novel, de novo experimental aims.

Body composition and metabolic factors

Body mass was measured to the nearest 0.1 kg. Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared. Fasting plasma lipid, lipoprotein, glucose, and insulin concentrations were determined using standard techniques.

EMV identification and isolation

EMV enumeration and isolation was performed as previously described.18 Briefly, venous blood was collected in sodium citrate tubes and centrifuged at 13,000 g for 2 minutes, and 200 μL was transferred to a TruCount tube (BD Biosciences, Franklin Lakes, NJ). EMVs phenotype was determined by incubating samples with fluorochrome-labeled antibodies (CD62e+; BioLegend, San Diego, CA) for 20 minutes at room temperature in a dark room. Samples were then fixed with 2% paraformaldehyde (ChemCruz Biochemicals, Santa Cruz, CA) and diluted with RNasefree PBS. EMV size threshold was established using Megamix-Plus SSC calibrator beads (Biocytex, Marseille, France), and only events >0.16 and <1 μm in size and CD62e+ were counted and subsequently collected. EMV concentration were determined by: (number of events in a region containing EMVs/number of events in absolute count bead region) × (total number of beads per test/total volume of sample).

EMV miRNA

Total RNA was isolated from EMVs using the miRNeasy FFPE Kit (Qiagen, Hilden, Germany) as previously described.19 To normalize for RNA content between samples, 3.5 μL (1.6 × 108 copies/μL) of Canorhabditis elegans miR-39 (cel-miR-39) was added during the RNA isolation. Immediately after isolation, 12 μL of total RNA was reverse transcribed using the miScript Reverse Transcription Kit (Qiagen). Complementary DNA was PCR amplified on the CFX96 (BioRad) RT-PCR platform using the miScript SYBR green PCR kit and miRNA-specific primers (Qiagen). All samples were assayed in duplicate. Relative expression (RE) per EMV for a given miRNA was normalized to cel-miR-39, calculated as RE = 2−Δ Ct/EMV = 2− [Ct[miRNA) – Ct(cel–miR–39)]/EMV and expressed as arbitrary units (AU).20

Statistical analysis

The distribution of the data was assessed by the Shapiro–Wilk test and the homogeneity of variances by the Levene test. Group differences in participant characteristics, circulating EMV concentration, and miR expression were determined by independent Student t test or Mann-Whitney U test. Data were presented as mean ± SEM for normally distributed variables and as the median (interquartile range [IQR]) for nonnormally distributed variables. Pearson correlations were determined between variables of interest. Statistical significance was set a priori at p < .05.

Results

Selected participant characteristics are presented in the Table 1. There were no statistically significant group differences in age, anthropometric, hemodynamic, or metabolic variables. Neither group demonstrated dyslipidemia, hyperinsulinemia, or high fasting glucose levels.21,22 Concentrations of circulating EMVs were significantly higher (~130%) in adults with SCI (138 ± 35 EMV/μL) compared with uninjured adults (60 ± 9 EMV/μL) (Figure 1).

Table 1.

Participant characteristics

Variable Uninjured (n = 8) SCI (n = 8)
Age, years 39±3 46±4
Male/Female 6M/2F 7M/1F
Time since injury, years 26±5
Body mass, kg 77.5±4.3 79.3±3.7
BMI, kg/m2 24.4±0.7 23.3±1.1
Systolic BP, mm Hg 113±4 117±3
Diastolic BP, mm Hg 69±4 72±4
Total cholesterol, mg/dL 131.6±9.1 157.0±9.3
LDL cholesterol, mg/dL 77.1±5.1 88.0±7.6
HDL cholesterol, mg/dL 43.2±3.2 45.9±4.8
Triglycerides, mg/dL 79.8±9.2 106.4±16.2
Glucose, mg/dL 91.1±6.7 86.5±3.6
Insulin, μU/mL 9.6±2.5 9.9±3.0
Open in a new tab

Note: BP = blood pressure; BMI = body mass index; HDL = high-density lipoprotein; LDL = low-density lipoprotein. Values are mean ± SEM. No variables met statistical significance of p < .05.

Figure 1.

Figure 1.

Open in a new tab

Circulating endothelial cell-derived microvesicles (EMVs) in uninjured and SCI adults. Mean value is denoted. *p < .05 vs. uninjured.

Expression levels of miR-30a, miR-126, miR-132, miR-145, miR-155, miR-216, and miR-Let-7a are shown in the Figure 2. Expression of miR-126 (mean ± SEM: 4.4 ± 1.0 vs. 6.9 ± 0.7 AU), miR-132 (median [IQR]: 0.6 [0.4–0.9] vs. 1.2 [0.8–1.5] AU), and miR-Let-7a (median [IQR]: 1.6 [1.3–3.5] vs. 3.5 [2.2–5.1] AU) were significantly lower (~100–150%); whereas, expression of miR-30a (mean ± SEM: 1.7 ± 0.2 vs. 1.1 ± 0.1 AU), miR-145 (mean ± SEM: 2.6 ± 0.4 vs. 1.6 ± 0.2 AU), miR-155 (mean+SEM: 1.4 ± 0.2 vs. 0.3 ± 0.1 AU), and miR-216 (median [IQR]: 2.2 [1.2–3.4] vs. 0.8 [0.5–1.1] AU) were significantly higher (~125–450%) in EMVs from adults with SCI compared with EMVs from uninjured adults. Within the SCI group there was no relation between time since injury and any miRNA.

Figure 2:

Figure 2:

Open in a new tab

MicroRNA (miRNA) expression in endothelial cell-derived microvesicles (EMVs) from uninjured and SCI adults: (A) miR-126, (B) miR-132, (C) miR-Let-7a, (D) miR-30a, (E) miR-145, (F) miR-155, and (G) miR-216. Mean value is denoted for miR-30a, miR-126, miR-145, and miR-155. Median value for miR-132, miR-216, and miR-7a. *p < .05 vs. uninjured.

Discussion

The novel finding of this study is the differential expression of a subset of vascular-related miRNA cargo in circulating EMVs isolated from adults with chronic SCI. Adults with SCI demonstrate unabating endothelial activation and inflammation, both of which are associated with increased extracellular vesicle release and altered cargo signature.23–25 In the present study, we demonstrate that SCI is not only associated with elevated circulating EMV levels but also an unfavorable EMV miRNA cargo signature. Indeed, the expression of miR-30a, miR-126, miR-132, miR-145, miR-155, miR-216, and miR-Let-7a was markedly more pathologic in EMVs from adults with SCI. The differential expression of each of these miRNAs has been mechanistically linked to increased risk, prevalence, and severity of vascular events.15,20,25–34 To our knowledge, this is the first study to determine the influence of SCI on elements of the miRNA cargo in circulating EMVs.

miRNAs are small noncoding RNAs that regulate posttranscriptional gene expression by targeting mRNA and, most often, repressing translation and/or inducing mRNA degradation.35 The ability of EMVs to transport and deliver miRNAs to recipient cells is a key factor underlying their cellular effects.36 Indeed, miRNAs packaged in EMVs are known to influence intercellular signaling pathways involved in endothelial inflammation, vasomotor regulation, apoptosis, and autophagy.27,37 Importantly, miRNAs carried by extracellular vesicles, such as EMVs, are more biologically active and predictive of atherosclerotic disease compared with freely circulating miRNAs in plasma.16 In a series of seminal studies, Jansen et al.15,16,27 reported that the miRNA signature in circulating EMVs could directly affect the vascular endothelium, promoting a pro-atherogenic endothelial phenotype. In addition, miRNA expression in EMVs has been shown to be independently predictive of adverse cardiac events in at-risk adults. In the present study, expression of miR-126, miR-132, and miR-Let-7a, three well-established anti-atherogenic, vasculoprotective miRNAs, were significantly lower (~100–150%) in EMVs from adults with SCI compared with EMVs from uninjured adults. Predominately expressed by endothelial cells, miR-126 reduces atherosclerotic lesion development by lowering the expression of proteins involved in endothelial cell activation and inflammation (such as vascular cell adhesion molecule-1, CXCL-12, and SPREAD-1) limiting endothelial inflammation and impeding lesion development and progression.11,14 Reduced cellular expression of miR-126 is associated with exaggerated inflammation, impaired nitric oxide production and, in turn, vasodilator dysfunction, loss of fibrinolytic potential, and reduced capacity for vascular repair.11,13 Clinically, in individuals with known coronary artery disease, lower levels of EMV miR-126 expression is associated with worsening atherosclerosis and more frequently required cardiac interventional procedures.27,31 Similarly, lower expression of miR-132 and miR-Let-7a is associated with accelerated development of small vessel disease, loss of cell integrity, and increased cell apoptotic susceptibility.38 For example, miR-132 suppresses MM-9 mRNA, limiting tight junction degradation and cell permeability.39 miR-132 has been proposed as a novel target for blood-brain barrier protection in ischemic stroke.39 miR-Let-7a targets caspase-3 mRNA29; reduced expression of miR-Let-7a allows for greater, less regulated, caspase-3 activation and inflated apoptosis.40 Reduced EMV cargo, and delivery, of these protective miRNAs amongst endothelial cells may contribute to SCI-related vasculature being more susceptible and prone to vascular events.

Further confounding lower miR-126, miR-132, and miR-Let-7a cargo, expression of miR-30a, miR-145, miR-155, and miR-216 was significantly higher (~125–450%) in EMVs from adults with SCI. Each of these miRNAs promote a pathogenic vascular phenotype.26,28,33,34,41–47 miR-30a inhibits cellular autophagy and is associated with reduced endothelial cell integrity and resistance to ischemic stress in multiple microvascular environments, including the blood-brain barrier.28,41–43 Similarly, miR-145 can disrupt autophagy and promote cell inflammation and apoptosis.26,44 Inhibiting miR-145 has been shown to reduce infarct volume in ischemic stroke models.45 miR-155 has also been linked with inflammation, premature cell death, and stroke risk.34 Indeed, miR-155 is associated with unregulated endothelial cell inflammation by limiting suppression of NF-kB activity and promoting oxidative stress and apoptosis.46,48,49,50 Both animal and clinical studies have demonstrated the importance of miR-155 in cerebrovascular events. In an ischemic stroke rat model, inhibition of miR-155 in brain endothelial cells was associated with reduced infarct size and improved neurorecovery.47 In patients with ischemic strokes, elevated expression of miR-155 in circulating EMVs was not only associated with onset, infarct volume, and clinical severity but was also predictive of clinical outcome.34 miR-216a is another proinflammatory mediator, suppressing Smad7 and resulting in reduced inhibition of NF-kB activation.51 In addition, miR-216a promotes endothelial cell senescence, autophagic dysfunction, and cell adhesion underlying its involvement in atherosclerotic plague progression and its clinical association with the development of coronary artery disease.51 Given the pathologic expression profile of these vascular-related microRNAs, circulating EMVs and their microRNA cargo may serve as a biomarker of risk and mechanistic factor underlying cardiovascular and cerebrovascular events with SCI.

Future studies are needed to address causal etiology and the potential of EMVs and their microRNA cargo as diagnostic and therapeutic targets of clinical relevance. Whether the presented differences in the miRNA cargo signature are clinically meaningful is unknown. Reference ranges for specific circulating miRNA and miRNA cargo in EMVs are not established in any populations, but its diagnostic value has been tested in non-SCI populations. For example, Zhang et al. demonstrated EMV + EMV-mir-155 concentration was predictive of individuals with and without ischemic strokes and superior in combination rather one or the other.34 Similar, future prospective studies will be needed to provide diagnostic value in SCI clinical practice.

There are other experimental considerations of the present study that deserve mention. Firstly, circulating EMVs and miRNA cargo are affected by a myriad of physiologic, pathologic, and behavioral factors24,25 that can compromise cross-sectional studies. There were no differences between groups in adiposity, risk factor profile, or incidence of cardiometabolic disease, thus the influence of these factors secondary to SCI on our results, we believe, is minimal. Secondly, the present study consisted of individuals with cervical levels of injury. We are unable to comment on the impact of other neurological level of injury or completeness of injury on EMV number and miRNA cargo. Given the heterogeneity of SCI with regard to level and completeness of injury, future studies are needed to more completely characterize the impact of SCI on circulating EMVs and their cargo. Thirdly, our study sample size is not sufficient to address population level differences in EMVs and/or miRNA cargo nor sufficiently sex-balanced, which precludes us from determining potential sex-related differences in EMV number or miRNA cargo in adults with SCI. We have previously demonstrated significant sex-related differences in EMV miRNA cargo in uninjured middle-aged adults,18 thus it is plausible that similar differences exist in adults with SCI.Future studies are needed to address this important question.

Conclusion

Adults with SCI develop vascular disease and sustain cardiovascular and cerebrovascular events earlier in life than uninjured adults of similar age.1,5–7 The mechanisms responsible for this increased morbidity burden is now recognized to extend beyond traditional risk factors. The results of this study suggest that the EMV cargo signature of vascular-related miRNAs may be adversely influenced by SCI, resulting in an EMV phenotype that has been shown to contribute to coronary artery disease and ischemic stroke. Elevated circulating EMVs and their miRNA cargo represent a novel biomarker of vascular risk and a potential target for intervention to mitigate vascular disease and events after SCI.

Acknowledgments

We thank all the participants in the study as well as the staff at the University of Colorado Anschutz Medical Campus ACI/ID Flow Core for their technical assistance.

Funding Statement

Financial Support This study was supported in part by a Seed Grant from the ICORD supported by the Blusson Integrated Cures Partnership (P. Ainslie), Canada Research Chairs program (P. Ainslie), National Institutes of Health awards HL077450 and HL107715 (C. DeSouza), and Craig Hospital Foundation (A. Park).

Footnotes

Conflicts of Interest

The authors declare no conflicts of interest.

REFERENCES

  • 1.Cragg JJ, Noonan VK, Krassioukov A, Borisoff J. Cardiovascular disease and spinal cord injury: Results from a national population health survey. Neurology . 2013;81(8):723–728. doi: 10.1212/WNL.0b013e3182a1aa68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Cragg JJ, Stone JA, Krassioukov AV. Management of cardiovascular disease risk factors in individuals with chronic spinal cord injury: An evidence-based review. J Neurotrauma . 2012;29(11):1999–2012. doi: 10.1089/neu.2012.2313. [DOI] [PubMed] [Google Scholar]
  • 3.Raguindin PF, Frankl G, Itodo OA et al. The neurological level of spinal cord injury and cardiovascular risk factors: A systematic review and meta-analysis. Spinal Cord . doi: 10.1038/s41393-021-00678-6. Open access. August 20, 2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Lee CS, Lu YH, Lee ST, Lin CC, Ding HJ. Evaluating the prevalence of silent coronary artery disease in asymptomatic patients with spinal cord injury. Int Heart J . 2006;47(3):325–330. doi: 10.1536/ihj.47.325. [DOI] [PubMed] [Google Scholar]
  • 5.Matos-Souza JR, Pithon KR, Ozahata TM, Gemignani T, Cliquet A, Jr, Nadruz W., Jr Carotid intima-media thickness is increased in patients with spinal cord injury independent of traditional cardiovascular risk factors. Atherosclerosis . 2009;202(1):29–31. doi: 10.1016/j.atherosclerosis.2008.04.013. [DOI] [PubMed] [Google Scholar]
  • 6.Matos-Souza JR, Pithon KR, Ozahata TM et al. Subclinical atherosclerosis is related to injury level but not to inflammatory parameters in spinal cord injury subjects. Spinal Cord . 2010;48(10):740–4. doi: 10.1038/sc.2010.12. [DOI] [PubMed] [Google Scholar]
  • 7.Orakzai SH, Orakzai RH, Ahmadi N et al. Measurement of coronary artery calcification by electron beam computerized tomography in persons with chronic spinal cord injury: evidence for increased atherosclerotic burden. Spinal Cord . 2007;45(12):775–9. doi: 10.1038/sj.sc.3102045. [DOI] [PubMed] [Google Scholar]
  • 8.Curtis AM, Edelberg J, Jonas R et al. Endothelial microparticles: Sophisticated vesicles modulating vascular function. Vascular Med . 2013;18(4):204–214. doi: 10.1177/1358863X13499773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Landers-Ramos RQ, Addison OA, Beamer B et al. Circulating microparticle concentrations across acute and chronic cardiovascular disease conditions. Physiol Rep . 2020;8(15):e14534. doi: 10.14814/phy2.14534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Simak J, Gelderman MP, Yu H, Wright V, Baird AE. Circulating endothelial microparticles in acute ischemic stroke: A link to severity, lesion volume and outcome. J Thromb Haemost . 2006;4(6):1296–302. doi: 10.1111/j.1538-7836.2006.01911.x. [DOI] [PubMed] [Google Scholar]
  • 11.Pan Q, He C, Liu H et al. Microvascular endothelial cells-derived microvesicles imply in ischemic stroke by modulating astrocyte and blood brain barrier function and cerebral blood flow. Mol Brain . 2016;9(1):63. doi: 10.1186/s13041-016-0243-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Stockelman KA, Hijmans JG, Bammert TD, Greiner JJ, Stauffer BL, DeSouza CA. Circulating endothelial cell derived microvesicles are elevated with hypertension and associated with endothelial dysfunction. Can J Physiol Pharmacol . 2020;98(8):557–561. doi: 10.1139/cjpp-2020-0044. [DOI] [PubMed] [Google Scholar]
  • 13.Shu Z, Tan J, Miao Y, Zhang Q. The role of microvesicles containing microRNAs in vascular endothelial dysfunction. J Cell Mol Med . 2019;23(12):7933–7945. doi: 10.1111/jcmm.14716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Das S, Halushka MK. Extracellular vesicle microRNA transfer in cardiovascular disease. Cardiovasc Pathol . 2015;24(4):199–206. doi: 10.1016/j.carpath.2015.04.007. [DOI] [PubMed] [Google Scholar]
  • 15.Jansen F, Yang X, Hoelscher M et al. Endothelial microparticle-mediated transfer of MicroRNA-126 promotes vascular endothelial cell repair via SPRED1 and is abrogated in glucose-damaged endothelial microparticles. Circulation . 2013;128(18):2026–2038. doi: 10.1161/CIRCULATIONAHA.113.001720. [DOI] [PubMed] [Google Scholar]
  • 16.Jansen F, Yang X, Proebsting S et al. MicroRNA expression in circulating microvesicles predicts cardiovascular events in patients with coronary artery disease. J Am Heart Assoc . 2014;3(6):e001249. doi: 10.1161/JAHA.114.001249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Coombs GB, Barak OF, Phillips AA et al. Acute heat stress reduces biomarkers of endothelial activation but not macro- or microvascular dysfunction in cervical spinal cord injury. Am J Physiol Heart Circ Physiol. 2019;316(3):H722–H733. doi: 10.1152/ajpheart.00693.2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Bammert TD, Hijmans JG, Kavlich PJ et al. Influence of sex on the number of circulating endothelial microparticles and microRNA expression in middle-aged adults. Exp Physiol . 2017;102(8):894–900. doi: 10.1113/EP086359. [DOI] [PubMed] [Google Scholar]
  • 19.Bammert TD, Hijmans JG, Reiakvam WR Biochem Biophys Res Commun . High glucose derived endothelial microparticles increase active caspase-3 and reduce microRNA-Let-7a expression in endothelial cells [published online ahead of print September 20, 2017] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Hao L, Wang XG, Cheng JD et al. The up-regulation of endothelin-1 and down-regulation of miRNA-125a-5p, -155, and -199a/b-3p in human atherosclerotic coronary artery. CardiovascPathol . 2014;23(4):217–223. doi: 10.1016/j.carpath.2014.03.009. [DOI] [PubMed] [Google Scholar]
  • 21.National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation . 2002;106(25):3143–3421. [PubMed] [Google Scholar]
  • 22.Zavaroni I, Bonora E, Pagliara M et al. Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med . 1989;320(11):702–706. doi: 10.1056/NEJM198903163201105. [DOI] [PubMed] [Google Scholar]
  • 23.Wang TD, Wang YH, Huang TS, Su TC, Pan SL, Chen SY. Circulating levels of markers of inflammation and endothelial activation are increased in men with chronic spinal cord injury. J Formos Med Assoc . 2007;106(11):919–928. doi: 10.1016/S0929-6646(08)60062-5. [DOI] [PubMed] [Google Scholar]
  • 24.Amabile N, Heiss C, Chang V et al. Increased CD62e(+) endothelial microparticle levels predict poor outcome in pulmonary hypertension patients. J Heart Lung Transplant . 2009;28(10):1081–1086. doi: 10.1016/j.healun.2009.06.005. [DOI] [PubMed] [Google Scholar]
  • 25.Werner N, Wassmann S, Ahlers P, Kosiol S, Nickenig G. Circulating CD31+/annexin V+ apoptotic microparticles correlate with coronary endothelial function in patients with coronary artery disease. Arterioscler Thromb Vasc Biol . 2006;26(1):112–116. doi: 10.1161/01.ATV.0000191634.13057.15. [DOI] [PubMed] [Google Scholar]
  • 26.Dai SH, Chen LJ, Qi WH et al. MicroRNA-145 inhibition upregulates SIRT1 and attenuates autophagy in a mouse model of lung ischemia/reperfusion injury via NF-kappaB-dependent Beclin 1. Transplantation . 2021;105(3):529–539. doi: 10.1097/TP.0000000000003435. [DOI] [PubMed] [Google Scholar]
  • 27.Jansen F, Stumpf T, Proebsting S et al. Intercellular transfer of miR-126-3p by endothelial microparticles reduces vascular smooth muscle cell proliferation and limits neointima formation by inhibiting LRP6. J Mol Cell Cardiol. 2017;104:43–52. doi: 10.1016/j.yjmcc.2016.12.005. [DOI] [PubMed] [Google Scholar]
  • 28.Li BB, Chen YL, Pang F. MicroRNA-30a targets ATG5 and attenuates airway fibrosis in asthma by suppressing autophagy. Inflammation . 2020;43(1):44–53. doi: 10.1007/s10753-019-01076-0. [DOI] [PubMed] [Google Scholar]
  • 29.Tsang WP, Kwok TT. Let-7a microRNA suppresses therapeutics-induced cancer cell death by targeting caspase-3. Apoptosis . 2008;13(10):1215–22. doi: 10.1007/s10495-008-0256-z. [DOI] [PubMed] [Google Scholar]
  • 30.Wang P, Shao BZ, Deng Z, Chen S, Yue Z, Miao CY. Autophagy in ischemic stroke. Prog Neurobiol . 2018;163–164:98–117. doi: 10.1016/j.pneurobio.2018.01.001. [DOI] [PubMed] [Google Scholar]
  • 31.Wang S, Aurora AB, Johnson BA et al. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell . 2008;15(2):261–271. doi: 10.1016/j.devcel.2008.07.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Xu Q, Liang Y, Liu X et al. miR132 inhibits high glucoseinduced vascular smooth muscle cell proliferation and migration by targeting E2F5. Mol Med Rep . 2019;20(2):2012–2020. doi: 10.3892/mmr.2019.10380. [DOI] [PubMed] [Google Scholar]
  • 33.Yang HH, Chen Y, Gao CY, Cui ZT, Yao JM. Protective effects of microRNA-126 on human cardiac microvascular endothelial cells against hypoxia/reoxygenation-induced injury and inflammatory response by activating PI3K/Akt/eNOS signaling pathway. Cell Physiol Biochem . 2017;42(2):506–518. doi: 10.1159/000477597. [DOI] [PubMed] [Google Scholar]
  • 34.Zhang H, Chen G, Qiu W et al. Plasma endothelial microvesicles and their carrying miRNA-155 serve as biomarkers for ischemic stroke. J Neurosci Res . 2020;98(11):2290–2301. doi: 10.1002/jnr.24696. [DOI] [PubMed] [Google Scholar]
  • 35.Bartel DP. MicroRNAs: Target recognition and regulatory functions. Cell . 2009;136(2):215–33. doi: 10.1016/j.cell.2009.01.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Mause SF, Weber C. Microparticles: Protagonists of a novel communication network for intercellular information exchange. Circ Res . 2010;107(9):1047–57. doi: 10.1161/CIRCRESAHA.110.226456. [DOI] [PubMed] [Google Scholar]
  • 37.Loyer X, Vion AC, Tedgui A, Boulanger CM. Microvesicles as cell-cell messengers in cardiovascular diseases. Circ Res . 2014;114(2):345–353. doi: 10.1161/CIRCRESAHA.113.300858. [DOI] [PubMed] [Google Scholar]
  • 38.Rawal S, Munasinghe PE, Shindikar A et al. Down-regulation of proangiogenic microRNA-126 and microRNA-132 are early modulators of diabetic cardiac microangiopathy. Cardiovasc Res . 2017;113(1):90–101. doi: 10.1093/cvr/cvw235. [DOI] [PubMed] [Google Scholar]
  • 39.Zuo X, Lu J, Manaenko A et al. MicroRNA-132 attenuates cerebral injury by protecting blood-brain-barrier in MCAO mice. Exp Neurol . 2019;316:12–19. doi: 10.1016/j.expneurol.2019.03.017. [DOI] [PubMed] [Google Scholar]
  • 40.Bao MH, Zhang YW, Lou XY, Cheng Y, Zhou HH. Protective effects of let-7a and let-7b on oxidized low-density lipoprotein induced endothelial cell injuries. PLoS One . 2014;9(9):e106540. doi: 10.1371/journal.pone.0106540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Bi R, Dai Y, Ma Z, Zhang S, Wang L, Lin Q. Endothelial cell autophagy in chronic intermittent hypoxia is impaired by miRNA-30a-mediated translational control of Beclin-1. J Cell Biochem . 2019;120(3):4214–4224. doi: 10.1002/jcb.27708. [DOI] [PubMed] [Google Scholar]
  • 42.Murinello S, Usui Y, Sakimoto S et al. miR-30a-5p inhibition promotes interaction of Fas(+) endothelial cells and FasL(+) microglia to decrease pathological neovascularization and promote physiological angiogenesis. Glia . 2019;67(2):332–344. doi: 10.1002/glia.23543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Wang P, Liang J, Li Y et al. Down-regulation of miRNA-30a alleviates cerebral ischemic injury through enhancing beclin 1-mediated autophagy. Neurochem Res. 2014;39(7):1279–1291. doi: 10.1007/s11064-014-1310-6. [DOI] [PubMed] [Google Scholar]
  • 44.Wu G, Tan J, Li J, Sun X, Du L, Tao S. J Cell Physiol . 2019. miRNA-145-5p induces apoptosis after ischemia-reperfusion by targeting dual specificity phosphatase 6. [DOI] [PubMed] [Google Scholar]
  • 45.Xie X, Peng L, Zhu J et al. miR-145-5p/Nurr1/TNF-alpha Signaling-induced microglia activation regulates neuron injury of acute cerebral ischemic/reperfusion in rats. Front Mol Neurosci . 2017;10:383. doi: 10.3389/fnmol.2017.00383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Liu Y, Pan Q, Zhao Y et al. MicroRNA-155 regulates ROS production, NO generation, apoptosis and multiple functions of human brain microvessel endothelial cells under physiological and pathological conditions. J Cell Biochem . 2015;116(12):2870–2881. doi: 10.1002/jcb.25234. [DOI] [PubMed] [Google Scholar]
  • 47.Xing G, Luo Z, Zhong C, Pan X, Xu X. Influence of miR-155 on cell apoptosis in rats with ischemic stroke: Role of the Ras homolog enriched in brain (Rheb)/mTOR pathway. Med Sci Monit . 2016;22:5141–5153. doi: 10.12659/msm.898980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Nazari-Jahantigh M, Wei Y, Noels H et al. MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages. J Clin Invest . 2012;122(11):4190–202. doi: 10.1172/JCI61716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Tili E, Michaille JJ, Cimino A et al. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol . 2007;179(8):5082–9. doi: 10.4049/jimmunol.179.8.5082. [DOI] [PubMed] [Google Scholar]
  • 50.Thompson RC, Herscovitch M, Zhao I, Ford TJ, Gilmore TD. NF-kappaB down-regulates expression of the B-lymphoma marker CD10 through a miR-155/PU.1 pathway. J Biol Chem . 2011;286(3):1675–82. doi: 10.1074/jbc.M110.177063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Yang S, Mi X, Chen Y et al. MicroRNA-216a induces endothelial senescence and inflammation via Smad3/IkappaBalpha pathway. J Cell Mol Med . 2018;22(5):2739–2749. doi: 10.1111/jcmm.13567. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Topics in Spinal Cord Injury Rehabilitation are provided here courtesy of American Spinal Injury Association

RESOURCES