title: Circulating Exosomes Induced by Cardiac Pressure Overload Contain Functional Angiotensin II Type 1 Receptors.
abstract: BACKGROUND
  Whether biomechanical force on the heart can induce exosome secretion to modulate cardiovascular function is not known. We investigated the secretion and activity of exosomes containing a key receptor in cardiovascular function, the angiotensin II type I receptor (AT1R).
  
  
  RESULTS
  Exosomes containing AT1Rs were isolated from the media overlying AT1R-overexpressing cells exposed to osmotic stretch and from sera of mice undergoing cardiac pressure overload. The presence of AT1Rs in exosomes was confirmed by both electron microscopy and radioligand receptor binding assays and shown to require β-arrestin2, a multifunctional adaptor protein essential for receptor trafficking. We show that functional AT1Rs are transferred via exosomes in an in vitro model of cellular stretch. Using mice with global and cardiomyocyte conditional deletion of β-arrestin2, we show that under conditions of in vivo pressure overload the cellular source of the exocytosis of exosomes containing AT1R is the cardiomyocyte. Exogenously administered AT1R-enriched exosomes target cardiomyocytes, skeletal myocytes, and mesenteric resistance vessels and are sufficient to confer blood pressure responsiveness to angiotensin II infusion in AT1R knockout mice.
  
  
  CONCLUSIONS
  AT1R-enriched exosomes are released from the heart under conditions of in vivo cellular stress to likely modulate vascular responses to neurohormonal stimulation. In the context of the whole organism, the concept of G protein-coupled receptor trafficking should consider circulating exosomes as part of the reservoir of functional AT1Rs.
authors.affiliation: From Departments of Medicine (G.P., R.T.S., D.A., S.M.-W.Y., M.C., W.C., K.H., L.M., L.J.W., H.A.R.), Cell Biology (H.A.R.), and Molecular Genetics and Microbiology (H.A.R.), Duke University Medical Center, Durham, NC.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Pironti
authors.affiliation: From Departments of Medicine (G.P., R.T.S., D.A., S.M.-W.Y., M.C., W.C., K.H., L.M., L.J.W., H.A.R.), Cell Biology (H.A.R.), and Molecular Genetics and Microbiology (H.A.R.), Duke University Medical Center, Durham, NC.
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Strachan
authors.affiliation: From Departments of Medicine (G.P., R.T.S., D.A., S.M.-W.Y., M.C., W.C., K.H., L.M., L.J.W., H.A.R.), Cell Biology (H.A.R.), and Molecular Genetics and Microbiology (H.A.R.), Duke University Medical Center, Durham, NC.
authors.forename: Dennis
authors.initials: D
authors.lastname: Abraham
authors.affiliation: From Departments of Medicine (G.P., R.T.S., D.A., S.M.-W.Y., M.C., W.C., K.H., L.M., L.J.W., H.A.R.), Cell Biology (H.A.R.), and Molecular Genetics and Microbiology (H.A.R.), Duke University Medical Center, Durham, NC.
authors.forename: Samuel
authors.initials: S
authors.lastname: Mon-Wei Yu
authors.affiliation: From Departments of Medicine (G.P., R.T.S., D.A., S.M.-W.Y., M.C., W.C., K.H., L.M., L.J.W., H.A.R.), Cell Biology (H.A.R.), and Molecular Genetics and Microbiology (H.A.R.), Duke University Medical Center, Durham, NC.
authors.forename: Minyong
authors.initials: M
authors.lastname: Chen
authors.affiliation: From Departments of Medicine (G.P., R.T.S., D.A., S.M.-W.Y., M.C., W.C., K.H., L.M., L.J.W., H.A.R.), Cell Biology (H.A.R.), and Molecular Genetics and Microbiology (H.A.R.), Duke University Medical Center, Durham, NC.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: From Departments of Medicine (G.P., R.T.S., D.A., S.M.-W.Y., M.C., W.C., K.H., L.M., L.J.W., H.A.R.), Cell Biology (H.A.R.), and Molecular Genetics and Microbiology (H.A.R.), Duke University Medical Center, Durham, NC.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hanada
authors.affiliation: From Departments of Medicine (G.P., R.T.S., D.A., S.M.-W.Y., M.C., W.C., K.H., L.M., L.J.W., H.A.R.), Cell Biology (H.A.R.), and Molecular Genetics and Microbiology (H.A.R.), Duke University Medical Center, Durham, NC.
authors.forename: Lan
authors.initials: L
authors.lastname: Mao
authors.affiliation: From Departments of Medicine (G.P., R.T.S., D.A., S.M.-W.Y., M.C., W.C., K.H., L.M., L.J.W., H.A.R.), Cell Biology (H.A.R.), and Molecular Genetics and Microbiology (H.A.R.), Duke University Medical Center, Durham, NC.
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Watson
authors.affiliation: From Departments of Medicine (G.P., R.T.S., D.A., S.M.-W.Y., M.C., W.C., K.H., L.M., L.J.W., H.A.R.), Cell Biology (H.A.R.), and Molecular Genetics and Microbiology (H.A.R.), Duke University Medical Center, Durham, NC. h.rockman@duke.edu.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rockman
mesh_terms: D000818:Animals; D019390:Arrestins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D001794:Blood Pressure; D003250:Constriction; D055354:Exosomes / Q000737:chemistry* / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D032342:Muscle Cells / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000737:chemistry* / Q000648:ultrastructure; D009997:Osmotic Pressure; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011869:Radioligand Assay; D044140:Receptor, Angiotensin, Type 1 / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D013314:Stress, Mechanical; D014655:Vascular Resistance; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; D000071557:beta-Arrestins
keywords: beta-arrestin; exosomes; hypertension; receptors, angiotensin; signal transduction