Gremlin Plays a Key Role in the Pathogenesis of Pulmonary Hypertension
Background—Pulmonary hypertension occurs in chronic hypoxic lung diseases, significantly worsening morbidity and mortality. The important role of altered bone morphogenetic protein (BMP) signaling in pulmonary hypertension was first suspected following the identification of heterozygous BMP receptor (BMPR) mutations as the underlying defect in the rare heritable form of pulmonary arterial hypertension (HPAH). Subsequently, it was demonstrated that BMP signaling was also reduced in common forms of pulmonary hypertension, including hypoxic pulmonary hypertension; however, the mechanism of this reduction has not previously been elucidated.
Methods and Results—Expression of two BMP antagonists, gremlin 1 and gremlin 2, was higher in the lung than in other organs and gremlin 1 was further increased in the walls of small intra-pulmonary vessels of mice during the development of hypoxic pulmonary hypertension. Hypoxia stimulated gremlin secretion from human pulmonary microvascular endothelial cells in vitro, which inhibited endothelial BMP signalling and BMP stimulated endothelial repair. Haplodeficiency of gremlin 1 augmented BMP signaling in the hypoxic mouse lung and reduced pulmonary vascular resistance by attenuating vascular remodelling. Furthermore, gremlin was increased in the walls of small intra-pulmonary vessels in idiopathic PAH and HPAH, in a distribution suggesting endothelial localization.
Conclusions—These findings demonstrate a central role for increased gremlin in hypoxia-induced pulmonary vascular remodeling and the increased pulmonary vascular resistance in hypoxic pulmonary hypertension. High levels of basal gremlin expression in the lung may account for the unique vulnerability of the pulmonary circulation to heterozygous mutations of BMPR2 in pulmonary arterial hypertension.
- Received April 15, 2011.
- Accepted December 28, 2011.
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