title: Gremlin plays a key role in the pathogenesis of pulmonary hypertension.
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.
  
  
  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.
authors.affiliation: University College Dublin, School of Medicine and Medical Sciences, Belfield, Dublin 4, Ireland.
authors.forename: Edwina
authors.initials: E
authors.lastname: Cahill
authors.forename: Christine M
authors.initials: CM
authors.lastname: Costello
authors.forename: Simon C
authors.initials: SC
authors.lastname: Rowan
authors.forename: Susan
authors.initials: S
authors.lastname: Harkin
authors.forename: Katherine
authors.initials: K
authors.lastname: Howell
authors.forename: Martin O
authors.initials: MO
authors.lastname: Leonard
authors.forename: Mark
authors.initials: M
authors.lastname: Southwood
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Cummins
authors.forename: Susan F
authors.initials: SF
authors.lastname: Fitzpatrick
authors.forename: Cormac T
authors.initials: CT
authors.lastname: Taylor
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.forename: Finian
authors.initials: F
authors.lastname: Martin
authors.forename: Paul
authors.initials: P
authors.lastname: McLoughlin
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000209:etiology*; D000860:Hypoxia / Q000150:complications; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000502:physiology*; D008297:Male; D051379:Mice; D015398:Signal Transduction; D014655:Vascular Resistance; D016207:Cytokines
chemical_list: D019485:Bone Morphogenetic Proteins; D036341:Intercellular Signaling Peptides and Proteins; C113178:Grem1 protein, mouse; D016207:Cytokines