Regulation of Endothelial Cell Permeability by Platelet-Derived Extracellular Vesicles.

BACKGROUND Platelet (Plt) derived-extracellular vesicles (Plt-EVs) have hemostatic properties similar to Plts. In addition to hemostasis, Plts also function to stabilize the vasculature and maintain endothelial cell (EC) barrier integrity. We hypothesized that Plt-EVs would inhibit vascular endothelial cell permeability, similar to fresh Plts. To investigate this hypothesis we utilized in vitro and in vivo models of vascular endothelial compromise and bleeding. METHODS In vitro: Plt-EVs were isolated by ultracentrifugation and characterized for Plt markers and particle size distribution. Effects of Plts and Plt-EVs on endothelial barrier function was assessed by trans - endothelial electrical resistance (TEER) measurements and histological analysis of endothelial junction proteins. Hemostatic potential of Plt-EVs and Plts were assessed by multiple electrode Plt aggregometry. In vivo: The effects of Plts and Plt-EVs on vascular permeability and bleeding were assessed in NOD-SCID mice by an established Miles Assay of vascular permeability and a tail snip bleeding assay. RESULTS In vitro: Plt-EVs displayed exosomal size distribution and expressed Plt specific surface markers. Plts and Plt-EVs decreased EC permeability and restored EC junctions after thrombin challenge. Multiplate aggregometry revealed that Plt-EVs enhanced Thrombin Receptor Activating Peptide (TRAP) mediated aggregation of whole blood, whereas Plts enhanced TRAP, Arachidonic Acid (ASPI), Collagen, and Adenosine Diphosphate (ADP) mediated aggregation. In vivo: Plt-EVs are equivalent to Plts in attenuating VEGF-A induced vascular permeability and uncontrolled blood loss in a tail snip hemorrhage model. CONCLUSION Our study is the first to report that Plt-EVs might provide a feasible product for transfusion in trauma patients to attenuate bleeding, inhibit vascular permeability and mitigate the endotheliopathy of trauma (EOT). STUDY TYPE Original Article LEVEL OF EVIDENCE: This is a pre-clinical study so it does not confirm to the level of evidence table for all clinical studies and case reports.

• Publication year

  2019

• Venue

  Journal of Trauma and Acute Care Surgery

• Publication date

  2019-06-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1097/TA.0000000000002230PMID 30768560PMCID PMC7381393
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

• Selective release of circRNAs in platelet-derived extracellular vesicles

  2018cited by this paper
• Platelet transfusions improve hemostasis and survival in a substudy of the prospective, randomized PROPPR trial.

  2018cited by this paper
• Rab27-Dependent Exosome Production Inhibits Chronic Inflammation and Enables Acute Responses to Inflammatory Stimuli

  2017cited by this paper
• Platelet-derived Extracellular Vesicles: An Emerging Therapeutic Approach

  2017cited by this paper
• Platelet-Derived Microvesicles: A Potential Therapy for Trauma-Induced Coagulopathy

  2017cited by this paper
• The effects of 22°C and 4°C storage of platelets on vascular endothelial integrity and function

  2016cited by this paper
• Modulating the endotheliopathy of trauma: Factor concentrate versus fresh frozen plasma

  2016cited by this paper
• Platelets regulate vascular endothelial stability: assessing the storage lesion and donor variability of apheresis platelets

  2016cited by this paper
• Techniques for the analysis of extracellular vesicles using flow cytometry.

  2015cited by this paper
• Fresh frozen plasma and spray-dried plasma mitigate pulmonary vascular permeability and inflammation in hemorrhagic shock

  2015cited by this paper
• Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper

  2015cited by this paper
• Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial.

  2015cited by this paper
• Biological properties of extracellular vesicles and their physiological functions

  2015cited by this paper
• Chromatographically isolated CD63+CD81+ extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI

  2015cited by this paper
• Mortality and ratio of blood products used in patients with severe trauma--reply.

  2015cited by this paper
• Microvesicle phenotypes are associated with transfusion requirements and mortality in subjects with severe injuries

  2015cited by this paper
• Isolation and characterization of platelet-derived extracellular vesicles

  2014cited by this paper
• Tetraspanins in Extracellular Vesicle Formation and Function

  2014cited by this paper
• Hemostatic Function of Apheresis Platelets Stored at 4°C and 22°C

  2014cited by this paper
• Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation.

  2014cited by this paper
• Optimal trauma resuscitation with plasma as the primary resuscitative fluid: the surgeon's perspective.

  2013cited by this paper
• GLOBAL HEALTH Injuries

  2013cited by this paper
• Extracellular vesicle sizing and enumeration by nanoparticle tracking analysis

  2013cited by this paper
• Advances in military, field, and austere transfusion medicine in the last decade.

  2013cited by this paper
• Thrombosomes: a platelet‐derived hemostatic agent for control of noncompressible hemorrhage

  2013cited by this paper
• Death on the battlefield (2001–2011): Implications for the future of combat casualty care

  2012cited by this paper
• Microparticles in Hemostasis and Thrombosis

  2011cited by this paper
• The platelet storage lesion.

  2010cited by this paper
• Exosomes: extracellular organelles important in intercellular communication.

  2010cited by this paper
• Exosomes Communicate Protective Messages during Oxidative Stress; Possible Role of Exosomal Shuttle RNA

  2010cited by this paper
• Membrane vesicles as conveyors of immune responses

  2009cited by this paper
• Exosomes: proteomic insights and diagnostic potential

  2009cited by this paper
• Injury severity and causes of death from Operation Iraqi Freedom and Operation Enduring Freedom: 2003-2004 versus 2006.

  2008cited by this paper
• Platelets, petechiae, and preservation of the vascular wall.

  2008cited by this paper
• Platelet microparticle membranes have 50- to 100-fold higher specific procoagulant activity than activated platelets

  2007cited by this paper
• Lyophilized Platelets: Fifty Years in the Making

  2007cited by this paper
• Isolation and Characterization of Exosomes from Cell Culture Supernatants and Biological Fluids

  2006cited by this paper
• Platelet storage lesion of WBC‐reduced, pooled, buffy coat‐derived platelet concentrates prepared in three in‐process filter/storage bag combinations

  2001cited by this paper
• Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules.

  1999cited by this paper
• Cell surface expression of lysosome‐associated membrane protein‐2 (lamp2) and CD63 as markers of in vivo platelet activation in malignancy

  1995cited by this paper
• Thrombospondin promotes platelet aggregation.

  1988cited by this paper
• Platelet Storage Lesion in Second‐Generation Containers: Correlation with Platelet ATP Levels

  1987cited by this paper

• Orthobiologics and Peptide Therapy for Central Nervous System Repair in Neurodegenerative Conditions

  2025cites this paper
• A Multiomic Study of Platelet-Derived Extracellular Vesicles and Impact of Platelet Concentrate Sources

  2025cites this paper
• Decoding the proteomic landscape of platelet extracellular vesicles: Implications for coagulation in burn patients.

  2025cites this paper
• Novel Roles and Therapeutic Approaches Linking Platelets and Megakaryocytes to Non-Hemostatic and Thrombotic Disease

  2025cites this paper
• Dried blood products: Current and potential uses in trauma

  2025cites this paper
• Platelet-derived microvesicles isolated from type-2 diabetes mellitus patients harbour an altered miRNA signature and drive MDA-MB-231 triple-negative breast cancer cell invasion

  2024cites this paper
• Activated platelet-derived exosomal LRG1 promotes multiple myeloma cell growth

  2024cites this paper
• Impact of donor pool size on the variability of platelet lysate-derived extracellular vesicles for regenerative medicine

  2024cites this paper
• Unleashing the biomimetic targeting potential of platelet-derived nanocarriers on atherosclerosis.

  2024cites this paper
• Unraveling the Impact of Extracellular Vesicle-Depleted Serum on Endothelial Cell Characteristics over Time

  2024cites this paper
• Exploring the Hemostatic Effects of Platelet Lysate-Derived Vesicles: Insights from Mouse Models

  2024influential citation
• Microvesicles derived from dermal myofibroblasts modify the integrity of the blood and lymphatic barriers using distinct endocytosis pathways

  2024cites this paper
• Induction of PD-1 and CD44 in CD4+ T cells by circulatory extracellular vesicles from severe dengue patients drives endothelial damage via the NF-kB signaling pathway

  2024cites this paper
• The potential utilization of platelet-derived extracellular vesicles in clinical treatment

  2024cites this paper
• Platelet extracellular vesicles preserve lymphatic endothelial cell integrity and enhance lymphatic vessel function

  2024cites this paper
• Serum from patients with cirrhosis undergoing liver transplantation induces permeability in human pulmonary microvascular endothelial cells ex vivo

  2024cites this paper
• Release of exosomes in polytraumatized patients: The injury pattern is reflected by the surface epitopes

  2023cites this paper
• Pilot study of frozen platelet extracellular vesicles as a therapeutic agent in hemorrhagic shock in rats

  2023cites this paper
• Haematopoietic cell‐derived exosomes in cancer development and therapeutics: From basic science to clinical practice

  2023cites this paper
• Advances in nanomaterial-based targeted drug delivery systems

  2023cites this paper
• A double-edged sword of platelet-derived extracellular vesicles in tissues, injury or repair: The current research overview.

  2023cites this paper
• Platelets, Protean Cells with All-Around Functions and Multifaceted Pharmacological Applications

  2023cites this paper
• Extracellular Vesicles and Atherosclerotic Peripheral Arterial Disease.

  2022cites this paper
• Targeting repair of the vascular endothelium and glycocalyx after traumatic injury with plasma and platelet resuscitation

  2022cites this paper
• Clinical Implementation of Platelet- and Extracellular Vesicle-Rich Product Preparation Protocols

  2022cites this paper
• Platelet Extracellular Vesicles Are Taken up by Canine T Lymphocytes but Do Not Play a Role in Their Proliferation, Differentiation and Cytokine Production In Vitro

  2022influential citation
• Pediatric platelet transfusions in critical illness: a narrative review of recent studies

  2022cites this paper
• Use of Cold-Stored Whole Blood is Associated With Improved Mortality in Hemostatic Resuscitation of Major Bleeding

  2022cites this paper
• Platelet Transfusion for Trauma Resuscitation

  2022cites this paper
• In vitro evaluation of platelet extracellular vesicles (PEVs) for corneal endothelial regeneration

  2022cites this paper
• TRAUMA-DERIVED EXTRACELLULAR VESICLES ARE SUFFICIENT TO INDUCE ENDOTHELIAL DYSFUNCTION AND COAGULOPATHY

  2022cites this paper
• Use of whole blood deployment programs for mass casualty incidents: South Texas experience in regional response and preparedness

  2022cites this paper
• The Pathophysiological Role of Platelet-Derived Extracellular Vesicles

  2022cites this paper
• Progression of hepatocellular carcinoma after radiofrequency ablation: Current status of research

  2022cites this paper
• Platelet-Derived Extracellular Vesicles for Regenerative Medicine

  2021cites this paper
• Endothelial Extracellular Vesicles: From Keepers of Health to Messengers of Disease

  2021cites this paper
• Extracellular vesicles in kidneys and their clinical potential in renal diseases

  2021cites this paper
• Landscape of extracellular vesicles in the tumour microenvironment: Interactions with stromal cells and with non-cell components, and impacts on metabolic reprogramming, horizontal transfer of neoplastic traits, and the emergence of therapeutic resistance.

  2021cites this paper
• Plasma Concentrations of Extracellular Vesicles Are Decreased in Patients with Post-Infarct Cardiac Remodelling

  2021cites this paper
• Trauma-induced pulmonary thromboembolism: What's update?

  2021cites this paper
• Characterization and Therapeutic Use of Extracellular Vesicles Derived from Platelets

  2021cites this paper
• Endothelial-Derived Extracellular Vesicles Induce Cerebrovascular Dysfunction in Inflammation

  2021cites this paper
• Extracellular vesicles as mediators and markers of acute organ injury: current concepts

  2021cites this paper
• Fluids of the Future

  2021cites this paper
• Platelets

  2020cites this paper
• Cell-derived biomimetic nanoparticles as a novel drug delivery system for atherosclerosis: predecessors and perspectives

  2020cites this paper
• Effect of platelet storage duration on clinical outcomes and incremental platelet change in critically ill children

  2020influential citation
• Extracellular Vesicles as Potential Prognostic Markers of Lymphatic Dysfunction

  2020cites this paper
• Contemporary resuscitation of hemorrhagic shock: What will the future hold?

  2020cites this paper
• Platelets and Fibrinogen: Emerging Complexity in Trauma-Induced Coagulopathy

  2020cites this paper
• Alterations in platelet behavior after major trauma: adaptive or maladaptive?

  2020cites this paper
• Prospective Therapeutic Applications of Platelet Extracellular Vesicles.

  2020cites this paper
• Defining and Assessing the Endotheliopathy of Trauma and Its Implications on Trauma-Induced Coagulopathy and Trauma-Related Outcomes

  2020cites this paper
• Freeze dried platelets promote clot formation, rescue thrombin induced endothelial cell permeability, and decrease pulmonary vascular leak in a murine model of hemorrhagic shock.

  2020cites this paper
• Extracellular vesicles: new players in regulating vascular barrier function

  2020cites this paper
• Platelet Extracellular Vesicles: Beyond the Blood.

  2020cites this paper
• Platelet-derived- Extracellular Vesicles Promote Hemostasis and Prevent the Development of Hemorrhagic Shock

  2019cites this paper
• Platelet Contributions to Trauma-Induced Coagulopathy: Updates in Post-injury Platelet Biology, Platelet Transfusions, and Emerging Platelet-Based Hemostatic Agents

  2019cites this paper
• The effect of platelet storage temperature on haemostatic, immune, and endothelial function: potential for personalised medicine.

  2019cites this paper
• Reciprocal enhancement of thrombosis by endothelial-to-mesenchymal transition induced by iliac vein compression.

  2019cites this paper
• Platelet-derived vesicles: diagnostic and predictive value in cardiovascular diseases

  2019cites this paper
• Extracellular Vesticles in Acute Respiratory Distress Syndrome: Extracellular Vesticles in Acute Respiratory Distress Syndrome: Understanding Protective and Harmful Signaling for the Understanding Protective and Harmful Signaling for the Development of New Therapeutics Development of New Therapeutic

  year unknowncites this paper