Proceedings of The Physiological Society
University of Birmingham (2010) Proc Physiol Soc 20, C06 and PC06
Hypoxic upregulation of the bone morphogenetic protein antagonist gremlin1 contributes to the development of pulmonary hypertension
S. Coyle-Rowan1, E. Cahill1, S. Harkin1, K. Howell1, F. Martin2, C. Costello1, P. McLoughlin1
1. School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland. 2. School of Biomolecular and Biomedical Sciences, University College Dublin, Dublin, Ireland.
Pulmonary hypertension is a common complication of chronic hypoxic lung diseases. Recently we reported that gremlin, a BMP antagonist, was selectively upregulated in hypoxic human pulmonary microvascular endothelial cells in vitro (Costello et al., 2008). Given the important role of bone morphogenetic proteins (BMP) in normal pulmonary vascular homeostasis, we postulated that upregulation of the BMP antagonist gremlin1 was an important pathogenic mechanism contributing to the development of hypoxic pulmonary hypertension. To test this hypothesis we exposed groups of wild type mice (N=10) and mice heterozygous (N=9) for a mutation in the gremlin1 gene (grem1+/-) to hypoxia (FIO2= 0.10) for a period of three weeks. Mice were then anaesthetised (sodium pentobarbitone 70mg.kg-1), anticoagulated, killed by exsanguination and the lungs immediately isolated, ventilated and perfused at constant flow with standard venous outflow and airway pressures such the pulmonary arterial pressure measurements were made in zone 3 conditions. Further lungs were fixed in paraformaldehyde at standard airway pressure and stained using a goat anti-gremlin antibody. Gremlin protein was expressed in the pulmonary vascular endothelium of normoxic and chronically hypoxic mice. Haematocrit was similarly elevated in the wild type and grem1+/- groups following hypoxic exposure. The mean (±SEM) ratio of right ventricular to left ventricular plus septal weight was significantly lower (P<0.05) in the chronically hypoxic grem1+/- mice (0.364±0.016) than in the wild types (0.432±0.022). Mean pulmonary arterial pressure in the grem1+/- mice (8.1±0.2 mmHg) was significantly lower (P<0.01) than that in the wild type mice (9.1±0.2 mmHg) following three weeks of hypoxia. These data show that heterozygous loss of gremlin attenuates the pulmonary vascular response to chronic hypoxia in mice and suggest a key role for this BMP antagonist in the development of hypoxic pulmonary hypertension similar to that found at high altitude and in chronic lung disease.
Where applicable, experiments conform with Society ethical requirements