title: The Osmopressor-Induced Angiopoietin-1 Secretion in Plasma and Subsequent Activation of the Tie-2/Akt/eNOS Signaling Pathway in Red Blood Cell.
abstract: BACKGROUND
  Water ingestion induces the osmopressor response, which typically presents as increased total peripheral vascular resistance in young healthy subjects. A previous study has suggested that the RBC membrane receptor is involved in osmopressor stress. Recent studies have indicated nitric oxide synthase phosphorylation in RBCs. However, the main process in signaling pathway activation to elicit such a response is unknown. Herein, we hypothesized that hypo-osmotic stress following water ingestion modulates the eNOS/NO pathway, thereby alternating vascular resistance.
  
  
  METHODS
  We included 24 young, healthy subjects. Physiological parameters and blood samples were collected at 5 minutes before and 25 and 50 minutes after 50 ml water, 500 ml water, or 500 ml normal saline ingestion. A human receptor tyrosine kinase (RTK) phosphorylation antibody array was used to simultaneously detect and monitor the biological activation pathways in RBCs.
  
  
  RESULTS
  Of the 71 RTKs assayed during the osmopressor response, several RTKs were significantly upregulated, including Tie-2 and Tie-1. Plasma angiopoietin-1 levels significantly increased at 25 minutes after 500 ml water ingestion compared to those at baseline. Simultaneous phosphorylation of Tie-2, Akt, and eNOS in RBCs occurred. RBCs in vitro were stimulated with angiopoietin-1, Tie-2, or 0.8% saline and showed significant increase in Tie-2, Akt, and eNOS phosphorylation upon angiopoietin-1 treatment and enhanced activation upon cotreatment of angiopoietin-1 and 0.8% saline.
  
  
  CONCLUSIONS
  The hypo-osmotic stimulus of water ingestion increases angiopoietin-1 secretion and subsequently activates the Tie-2/Akt/eNOS signaling pathway in RBCs, thereby revealing a novel biological mechanism simultaneously occurring with the osmopressor response.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: You-Hsiang
authors.initials: YH
authors.lastname: Chu
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Institute of Aerospace Medicine, National Defense Medical Center, Taipei, Taiwan.|Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chih-Cherng
authors.initials: CC
authors.lastname: Lu
authors.affiliation: Department of Anesthesiology, Tri-Service General Hospital, Taipei, Taiwan.
authors.forename: Tso-Chou
authors.initials: TC
authors.lastname: Lin
authors.affiliation: Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Mei-Yung
authors.initials: MY
authors.lastname: Tsou
authors.affiliation: Division of Nephrology and Department of Medicine, National Defense Medical Center, Taipei, Taiwan.|Department of Nephrology of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan.
authors.forename: Yu-Juei
authors.initials: YJ
authors.lastname: Hsu
authors.affiliation: Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Anesthesiology, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Shung-Tai
authors.initials: ST
authors.lastname: Ho
authors.affiliation: Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan.|Division of Medical Research and Education, Cheng-Hsin General Hospital, Taipei, Taiwan.
authors.forename: Che-Se
authors.initials: CS
authors.lastname: Tung
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Ching-Jiunn
authors.initials: CJ
authors.lastname: Tseng
authors.affiliation: Institute of Aerospace Medicine, National Defense Medical Center, Taipei, Taiwan.|Department of Physical Medicine and Rehabilitation, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Min-Hui
authors.initials: MH
authors.lastname: Li
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Herng-Sheng
authors.initials: HS
authors.lastname: Lee
mesh_terms: D042683:Angiopoietin-1 / Q000097:blood*; D000906:Antibodies / Q000032:analysis; D051398:Aquaporin 1 / Q000378:metabolism; D018592:Cross-Over Studies; D004912:Erythrocytes / Q000187:drug effects*; D064368:Healthy Volunteers; D006439:Hemodynamics; D006801:Humans; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects*; D051058:Oncogene Protein v-akt / Q000187:drug effects*; D009997:Osmotic Pressure / Q000187:drug effects*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000276:immunology; D042787:Receptor, TIE-2 / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D014655:Vascular Resistance / Q000187:drug effects; D014867:Water; D055815:Young Adult
chemical_list: C467630:ANGPT1 protein, human; C496020:AQP1 protein, human; D042683:Angiopoietin-1; D000906:Antibodies; D014867:Water; D051398:Aquaporin 1; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D011505:Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; D051058:Oncogene Protein v-akt
keywords: Tie-2 receptor.; angiopoietin-1; blood pressure; endothelial nitric oxide synthase; erythrocytes; hypertension; osmopressor response