Research

Effects of bone marrow-derived cells on monocrotaline- and hypoxia-induced pulmonary hypertension in mice

William Raoul¹ , Orianne Wagner-Ballon⁶ , Guitanouch Saber¹ , Anne Hulin⁵ , Elisabeth Marcos¹ , Stéphane Giraudier^2,6 , William Vainchenker² , Serge Adnot^1,3 , Saadia Eddahibi¹ and Bernard Maitre^1,3,4

¹Unité INSERM TGU841 – Université Paris XII, Créteil, France

²Unité INSERM U362 – Institut Gustave Roussy, Villejuif, France

³Unité de Pneumologie – Hôpital Henri Mondor, AP-HP, Créteil, France

⁴Service de Physiologie – Hôpital Henri Mondor, AP-HP, Créteil, France

⁵Service de Toxicologie-Pharmacologie, Hôpital Henri Mondor, AP-HP, Créteil, France

⁶Service d'Hématologie – Hôpital Henri Mondor, AP-HP, Créteil, France

author email corresponding author email

Respiratory Research 2007, 8:8doi:10.1186/1465-9921-8-8

Published:	30 January 2007

Abstract

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.

Objectives

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 ≤ 0.01), right ventricle weight/left ventricle+septum weight ratio (0.29 ± 0.02 vs. 0.36 ± 0.01, P ≤ 0.03), and percentage of muscularized vessels (26.4% vs. 33.5%, P ≤ 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.

Conclusion

These results show that BMDCs limit pulmonary vascular remodeling induced by vascular injury but not by hypoxia.