Dominant negative mutation of the TGF-beta receptor blocks hypoxia-induced pulmonary vascular remodeling

1 Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine, 2 Department of Cell Biology, and Division of Neonatology, 3 Department of Pediatrics, Birmingham, Alabama Submitted 19 May 2005 ; accepted in final form 7 October 2005 The present study utilized...

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Published in:Journal of applied physiology (1985) 2006-02, Vol.100 (2), p.564-571
Main Authors: Chen, Yiu-Fai, Feng, Ji-An, Li, Peng, Xing, Dongqi, Zhang, Yun, Serra, Rosa, Ambalavanan, Namasivayam, Majid-Hassan, Erum, Oparil, Suzanne
Format: Article
Language:English
Subjects:
Actins - metabolism
Animals
Biological and medical sciences
Blood pressure
Circulatory system
Collagen - genetics
Collagen - metabolism
Cytokines
Disease Models, Animal
Extracellular Matrix - metabolism
Fibronectins - metabolism
Fundamental and applied biological sciences. Psychology
Hypertension, Pulmonary - etiology
Hypertension, Pulmonary - metabolism
Hypertension, Pulmonary - pathology
Hypertrophy, Right Ventricular - etiology
Hypertrophy, Right Ventricular - metabolism
Hypoxia - complications
Hypoxia - metabolism
Hypoxia - pathology
Lungs
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Muscle, Smooth, Vascular - metabolism
Muscle, Smooth, Vascular - pathology
Mutation
Protein-Serine-Threonine Kinases
Pulmonary Alveoli - metabolism
Pulmonary Alveoli - pathology
Pulmonary Artery - metabolism
Pulmonary Artery - pathology
Pulmonary Circulation
Receptors, Transforming Growth Factor beta - deficiency
Receptors, Transforming Growth Factor beta - genetics
Receptors, Transforming Growth Factor beta - metabolism
Respiratory system
RNA, Messenger - metabolism
Signal Transduction
Transgenic animals
Ventricular Pressure
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Summary:1 Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine, 2 Department of Cell Biology, and Division of Neonatology, 3 Department of Pediatrics, Birmingham, Alabama Submitted 19 May 2005 ; accepted in final form 7 October 2005 The present study utilized a novel transgenic mouse model that expresses an inducible dominant negative mutation of the transforming growth factor (TGF)- type II receptor (DnTGF RII mouse) to test the hypothesis that TGF- signaling plays an important role in the pathogenesis of chronic hypoxia-induced increases in pulmonary arterial pressure and vascular and alveolar remodeling. Nine- to 10-wk-old male DnTGF RII and control nontransgenic (NTG) mice were exposed to normobaric hypoxia (10% O 2 ) or air for 6 wk. Expression of DnTGF RII was induced by drinking 25 mM ZnSO 4 water beginning 1 wk before hypoxic exposure. Hypoxia-induced increases in right ventricular pressure, right ventricular mass, pulmonary arterial remodeling, and muscularization were greatly attenuated in DnTGF RII mice compared with NTG controls. Furthermore, the stimulatory effects of hypoxic exposure on pulmonary arterial and alveolar collagen content, appearance of -smooth muscle actin-positive cells in alveolar parenchyma, and expression of extracellular matrix molecule (including collagen I and III, periostin, and osteopontin) mRNA in whole lung were abrogated in DnTGF RII mice compared with NTG controls. Hypoxic exposure had no effect on systemic arterial pressure or heart rate in either strain. These data support the hypothesis that endogenous TGF- plays an important role in pulmonary vascular adaptation to chronic hypoxia and that disruption of TGF- signaling attenuates hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, pulmonary arterial hypertrophy and muscularization, alveolar remodeling, and expression of extracellular matrix mRNA in whole lung. transforming growth factor; vascular hypertrophy and muscularization; alveolar remodeling; extracellular matrix Address for reprint requests and other correspondence: Y.-F. Chen, 1008 Zeigler Research Bldg., Dept. of Medicine, Univ. of Alabama at Birmingham, UAB Station, Birmingham, AL 35294-0007 (e-mail: yfchen{at}uab.edu )
ISSN:8750-7587
1522-1601
DOI:10.1152/japplphysiol.00595.2005