Effects of bone marrow-derived cells on monocrotaline- and hypoxia-induced pulmonary hypertension in mice.
BACKGROUND
Bone marrow -derived cells (BMDCs) can either limit or contribute to the process of pulmonary vascular remodeling. Whether the difference in their effects depends on the mechanism of pulmonary hypertension (PH) remains unknown.


OBJECTIVE
We investigated the effect of BMDCs on PH induced in mice by either monocrotaline or exposure to chronic hypoxia.


METHODS
Intravenous administration of the active monocrotaline metabolite (monocrotaline pyrrole, MCTp) to C57BL/6 mice induced PH within 15 days, due to remodeling of small distal vessels. Three days after the MCTp injection, the mice were injected with BMDCs harvested from femurs and tibias of donor mice treated with 5-fluorouracil (3.5 mg IP/animal) to deplete mature cells and to allow proliferation of progenitor cells.


RESULTS
BMDCs significantly attenuated PH as assessed by reductions in right ventricular systolic pressure (20 +/- 1 mmHg vs. 27 +/- 1 mmHg, P < or = 0.01), right ventricle weight/left ventricle+septum weight ratio (0.29 +/- 0.02 vs. 0.36 +/- 0.01, P < or = 0.03), and percentage of muscularized vessels (26.4% vs. 33.5%, P < or = 0.05), compared to control animals treated with irradiated BMDCs. Tracking cells from constitutive GFP-expressing male donor mice with anti-GFP antibodies or chromosome Y level measurement by quantitative real-time PCR showed BMDCs in the lung. In contrast, chronically hypoxic mice subjected to the same procedure failed to show improvement in PH.


CONCLUSIONS
These results show that BMDCs limit pulmonary vascular remodeling induced by vascular injury but not by hypoxia.
Raoul
William
W
Unité INSERM TGU841--Université Paris XII, Créteil, France. william.raoul@creteil.inserm.fr
Wagner-Ballon
Orianne
O
Saber
Guitanouch
G
Hulin
Anne
A
Marcos
Elisabeth
E
Giraudier
Stéphane
S
Vainchenker
William
W
Adnot
Serge
S
Eddahibi
Saadia
S
Maitre
Bernard
B
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006352:Heart Ventricles / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D000860:Hypoxia / Q000150:complications; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016686:Monocrotaline / Q000031:analogs & derivatives; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D011651:Pulmonary Artery / Q000473:pathology; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism; D013997:Time Factors; D016278:Ventricular Function, Right; D017725:Ventricular Pressure
C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C014114:monocrotaline pyrrole; D016686:Monocrotaline; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse