Type

Journal Article

Authors

Paul McLoughlin
Finian Martin
Nicholas W Morrell
Cormac T. Taylor
Susan F. Fitzpatrick
Eoin P. Cummins
Mark Southwood
Simon C. Rowan
Martin O Leonard
Christine M. Costello
and 3 others

Subjects

Pharmacology

Topics
microvascular endothelial cells pulmonary anoxia complications signal transduction animals endothelium cells cultured mice male etiology vascular resistance chronic obstructive pulmonary disease intercellular signaling peptides and proteins pulmonary vascular resistance grem1 protein mouse endothelial cells bone morphogenetic proteins metabolism hypertension hypertension pulmonary physiology hypoxia immunohistochemistry

Gremlin Plays a Key Role in the Pathogenesis of Pulmonary Hypertension (2012)

Abstract 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 after the identification of heterozygous BMP receptor mutations as the underlying defect in the rare heritable form of pulmonary arterial hypertension. 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 2 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 intrapulmonary 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 signaling 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 remodeling. Furthermore, gremlin was increased in the walls of small intrapulmonary vessels in idiopathic pulmonary arterial hypertension and the rare heritable form of pulmonary arterial hypertension 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 BMP type 2 receptor in pulmonary arterial hypertension.
Collections Ireland -> University College Dublin -> Systems Biology Ireland
Ireland -> University College Dublin -> Institutes and Centres
Ireland -> University College Dublin -> Conway Institute Research Collection
Ireland -> University College Dublin -> SBI Research Collection
Ireland -> University College Dublin -> Conway Institute

Full list of authors on original publication

Paul McLoughlin, Finian Martin, Nicholas W Morrell, Cormac T. Taylor, Susan F. Fitzpatrick, Eoin P. Cummins, Mark Southwood, Simon C. Rowan, Martin O Leonard, Christine M. Costello and 3 others

Experts in our system

1
Paul McLoughlin
University College Dublin
 
2
Finian Martin
University College Dublin
Total Publications: 81
 
3
Cormac T. Taylor
University College Dublin
Total Publications: 110
 
4
Susan F. Fitzpatrick
University College Dublin
Total Publications: 9
 
5
Eoin P. Cummins
University College Dublin
Total Publications: 53
 
6
Simon C. Rowan
University College Dublin
Total Publications: 7