BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia.
Heterozygous mutations of the bone morphogenetic protein type II receptor (BMPR-II) gene have been identified in patients with primary pulmonary hypertension. The mechanisms by which these mutations contribute to the pathogenesis of primary pulmonary hypertension are not fully elucidated. To assess the impact of a heterozygous mutation of the BMPR-II gene on the pulmonary vasculature, we studied mice carrying a mutant BMPR-II allele lacking exons 4 and 5 (BMPR-II(+/-) mice). BMPR-II(+/-) mice had increased mean pulmonary arterial pressure and pulmonary vascular resistance compared with their wild-type littermates. Histological analyses revealed that the wall thickness of muscularized pulmonary arteries (<100 mum in diameter) and the number of alveolar-capillary units were greater in BMPR-II(+/-) than in wild-type mice. Breathing 11% oxygen for 3 wk increased mean pulmonary arterial pressure, pulmonary vascular resistance, and hemoglobin concentration to similar levels in BMPR-II(+/-) and wild-type mice, but the degree of muscularization of small pulmonary arteries and formation of alveolar-capillary units were reduced in BMPR-II(+/-) mice. Our results suggest that, in mice, mutation of one copy of the BMPR-II gene causes pulmonary hypertension but impairs the ability of the pulmonary vasculature to remodel in response to prolonged hypoxic breathing.
Beppu
Hideyuki
H
Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. beppu@cvrc.mgh.harvard.edu).
Ichinose
Fumito
F
Kawai
Noriko
N
Jones
Rosemary C
RC
Yu
Paul B
PB
Zapol
Warren M
WM
Miyazono
Kohei
K
Li
En
E
Bloch
Kenneth D
KD
D000818:Animals; D001160:Arterioles / Q000502:physiology / Q000503:physiopathology; D052006:Bone Morphogenetic Protein Receptors, Type II; D005091:Exons / Q000235:genetics; D006580:Genetic Carrier Screening; D006976:Hypertension, Pulmonary / Q000235:genetics*; D000860:Hypoxia / Q000503:physiopathology*; D008168:Lung / Q000502:physiology* / Q000503:physiopathology; D051379:Mice; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011652:Pulmonary Circulation / Q000235:genetics / Q000502:physiology*; D017384:Sequence Deletion; D014655:Vascular Resistance / Q000235:genetics / Q000502:physiology
D017346:Protein Serine-Threonine Kinases; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II