title: Bone marrow-derived cells contribute to pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension.
abstract: OBJECTIVE
  In these days, it was reported that bone marrow (BM) cells might take part in the remodeling of some systemic vascular diseases; however, it remains unknown whether the BM cells were involved in the vascular remodeling of pulmonary arteries and the progression of pulmonary hypertension (PH). The purpose of this study was to investigate whether BM-derived cells contribute to pulmonary vascular remodeling in hypoxia-induced PH.
  
  
  METHODS
  To investigate the role of BM-derived cells, we transplanted the whole BM of enhanced green fluorescent protein (GFP)-transgenic mice to the lethally irradiated syngeneic mice (n = 30). After 8 weeks, chimera mice were exposed to consistent hypoxia using a hypoxic chamber (10% O(2)) for up to 4 or 8 weeks (10 mice per group). After hemodynamics and the ratio of right ventricular (RV) weight to left ventricle (LV) weight, RV/(LV + septum [S]), were measured, histologic and immunofluorescent staining were performed.
  
  
  RESULTS
  BM-transplanted mice showed a high chimerism (mean [+/- SEM], 91 +/- 2.3%). RV systolic pressure and the RV/(LV + S) ratio increased significantly with time in PH mice, indicating RV hypertrophy. Marked vascular remodeling including medial hypertrophy and adventitial proliferation was observed in the pulmonary arteries of PH mice. Strikingly, a number of GFP(+) cells were observed at the pulmonary arterial wall, including the adventitia, in hypoxia-induced PH mice, while very few cells were observed in the control mice. Metaspectrometer measurements using confocal laser scanning microscopy confirmed that this green fluorescence was produced by GFP, suggesting that these GFP(+) cells were mobilized from the BM. Most of them expressed alpha-smooth muscle actin, a smooth muscle cell, or myofibroblast phenotype, and contributed to the pulmonary vascular remodeling. A semiquantitative polymerase chain reaction of the GFP gene revealed that the BM-derived GFP-positive cells in the PH group were observed more than eightfold as often compared with the control mice.
  
  
  CONCLUSIONS
  The BM-derived cells mobilize to the hypertensive pulmonary arteries and contribute to the pulmonary vascular remodeling in hypoxia-induced PH mice.
authors.affiliation: Cardiopulmonary Division, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hayashida
authors.forename: Jun
authors.initials: J
authors.lastname: Fujita
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Miyake
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawada
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D002454:Cell Differentiation; D006976:Hypertension, Pulmonary / Q000473:pathology* / Q000503:physiopathology; D000860:Hypoxia; D051379:Mice; D008810:Mice, Inbred C57BL; D011651:Pulmonary Artery / Q000473:pathology* / Q000503:physiopathology