title: Induction of pulmonary hypertensive changes by extracellular vesicles from monocrotaline-treated mice.
abstract: OBJECTIVE
  Circulating endothelium-derived extracellular vesicles (EV) levels are altered in pulmonary arterial hypertension (PAH) but whether they are biomarkers of cellular injury or participants in disease pathogenesis is unknown. Previously, we found that lung-derived EVs (LEVs) induce bone marrow-derived progenitor cells to express lung-specific mRNA and protein. In this study, we sought to determine whether LEV or plasma-derived EV (PEV) alter pulmonary vascular endothelial or marrow progenitor cell phenotype to induce pulmonary vascular remodelling.
  
  
  RESULTS
  LEV, PEV isolated from monocrotaline (MCT-EV)- or vehicle-treated mice (vehicle-EV) were injected into healthy mice. Right ventricular (RV) hypertrophy and pulmonary vascular remodelling were assessed by RV-to-body weight (RV/BW) and blood vessel wall thickness-to-diameter (WT/D) ratios. RV/BW, WT/D ratios were elevated in MCT- vs. vehicle-injected mice (1.99 ± 0.09 vs. 1.04 ± 0.09 mg/g; 0.159 ± 0.002 vs. 0.062 ± 0.009%). RV/BW, WT/D ratios were higher in mice injected with MCT-EV vs. mice injected with vehicle-EV (1.63 ± 0.09 vs. 1.08 ± 0.09 mg/g; 0.113 ± 0.02 vs. 0.056 ± 0.01%). Lineage-depleted bone marrow cells incubated with MCT-EV and marrow cells isolated from mice infused with MCT-EV had greater expression of endothelial progenitor cell mRNAs and mRNAs abnormally expressed in PAH than cells incubated with vehicle-EV or isolated from vehicle-EV infused mice. MCT-EV induced an apoptosis-resistant phenotype in murine pulmonary endothelial cells and lineage-depleted bone marrow cells incubated with MCT-EV induced pulmonary hypertension when injected into healthy mice.
  
  
  CONCLUSIONS
  EV from MCT-injured mice contribute to the development of MCT-induced pulmonary hypertension. This effect may be mediated directly by EV on the pulmonary vasculature or by differentiation of bone marrow cells to endothelial progenitor cells that induce pulmonary vascular remodelling.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Rhode Island Hospital, Providence, RI 02908, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Aliotta
authors.forename: Mandy
authors.initials: M
authors.lastname: Pereira
authors.forename: Ashley
authors.initials: A
authors.lastname: Amaral
authors.forename: Arina
authors.initials: A
authors.lastname: Sorokina
authors.forename: Zenas
authors.initials: Z
authors.lastname: Igbinoba
authors.forename: Alexander
authors.initials: A
authors.lastname: Hasslinger
authors.forename: Rabih
authors.initials: R
authors.lastname: El-Bizri
authors.forename: Sharon I
authors.initials: SI
authors.lastname: Rounds
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Quesenberry
authors.forename: James R
authors.initials: JR
authors.lastname: Klinger
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D065627:Familial Primary Pulmonary Hypertension; D006976:Hypertension, Pulmonary / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000378:metabolism; D008168:Lung / Q000098:blood supply*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism; D016686:Monocrotaline; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D022161:Transport Vesicles / Q000378:metabolism* / Q000473:pathology
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D016686:Monocrotaline
keywords: Bone marrow stem/progenitor cells; Endothelium; Microparticles; Monocrotaline; Pulmonary hypertension