title: Mesenchymal stem cells attenuate hypoxic pulmonary vasoconstriction by a paracrine mechanism.
abstract: BACKGROUND
  Hypoxic pulmonary vasoconstriction (HPV) may be an adaptive mechanism to correct ventilation-perfusion mismatch in the face of hypoxia. In chronic hypoxia, prolonged vasoconstriction may result in pulmonary hypertension and cor pulmonale. It has been shown that during chronic hypoxia, mesenchymal stem cells (MSCs) may contribute to pulmonary vascular remodeling, anti-inflammation, and vascular stability. Also, MSCs have been shown to release growth factors when stressed by hypoxia. We hypothesized that MSCs reduce HPV by a paracrine mechanism. To test this, MSCs were stressed by hypoxia in tissue culture and the cell-free media was then used to treat the pulmonary arteries subjected to HPV.
  
  
  METHODS
  Adult male (250-350 g) Sprague Dawley rat pulmonary arteries (n = 10/group) were isolated and suspended in physiological organ baths. Human MSCs were stressed with 60-min hypoxia and conditioned media was collected. Pulmonary artery rings were treated with vehicle or MSC-conditioned (cell-free) media prior to hypoxia. Force displacement was continuously recorded. Data (mean +/- SEM) were analyzed with two-way analysis of variance with post-hoc Bonferroni test.
  
  
  RESULTS
  Pulmonary arteries exposed to MSC-conditioned media experienced an augmented vasodilatory phase as compared to vehicle. Maximum vasodilation was 53.58 +/- 6.42% versus 39.76 +/- 4.05% for vehicle (P < 0.001). In addition, delayed, phase II vasoconstriction was significantly attenuated as compared to vehicle. Maximum phase II vasoconstriction was 28.51 +/- 12.42 versus 86.29 +/- 15.99% for vehicle (P < 0.001).
  
  
  CONCLUSIONS
  We conclude that acute hypoxia induces HPV and that MSC-conditioned media acutely attenuates this effect. Thus, in addition to a direct contribution to vessel remodeling in chronic hypoxia, MSCs may acutely protect and attenuate hypoxic pulmonary vasoreactivity through a paracrine mechanism.
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Ketan M
authors.initials: KM
authors.lastname: Patel
authors.forename: Paul
authors.initials: P
authors.lastname: Crisostomo
authors.forename: Tim
authors.initials: T
authors.lastname: Lahm
authors.forename: Troy
authors.initials: T
authors.lastname: Markel
authors.forename: Christine
authors.initials: C
authors.lastname: Herring
authors.forename: Meijing
authors.initials: M
authors.lastname: Wang
authors.forename: Kirstan K
authors.initials: KK
authors.lastname: Meldrum
authors.forename: Keith D
authors.initials: KD
authors.lastname: Lillemoe
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Meldrum
mesh_terms: D000208:Acute Disease; D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D009924:Organ Culture Techniques; D019899:Paracrine Communication / Q000502:physiology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D017077:Culture Media, Conditioned