Submitted on December 26, 2007
Accepted on May 11, 2008
Transforming growth factor-beta signaling mediates hypoxia-induced pulmonary arterial remodeling and inhibition of alveolar development in newborn mouse lung
Namasivayam Ambalavanan1*, Teodora Nicola2, James Hagood3, Arlene Bulger3, Rosa Serra4, Joanne E. Murphy-Ullrich5, Suzanne Oparil6, and Yiu-Fai Chen7
1 Pediatrics, Cell Biology, and Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States
2 Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, United States
3 Pediatrics, University of Alabama-Birmingham, Birmingham, Alabama, United States
4 Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States
5 Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States
6 Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States
7 Vascular Biology and Hypertension Program, 1008 Zeigler Research Building, Birmingham,, Alabama, United States
* To whom correspondence should be addressed. E-mail: nambalavanan{at}peds.uab.edu.
Hypoxia causes abnormal neonatal pulmonary artery remodeling (PAR) and inhibition of alveolar development (IAD). Transforming growth factor-
(TGF-) is an important regulator of lung development and repair from injury. We tested the hypothesis that inhibition of TGF- signaling attenuates hypoxia-induced PAR and IAD. Mice with an inducible dominant negative mutation of the TGF- type II receptor (DNTGFRII) and non-transgenic wild-type (WT) mice were exposed to hypoxia (12% O2) or air from birth to 14 days of age. Expression of DNTGFRII was induced by 20 µg/g ZnSO4 i.p. daily from birth. PAR, IAD, cell proliferation, and expression of extracellular matrix (ECM) proteins were assessed. In WT mice, hypoxia led to thicker, more muscularized pulmonary arteries and impaired alveolarization, accompanied by increases in active TGF- and phosphorylated Smad2. Hypoxia-induced PAR and IAD were attenuated in DNTGFRII mice given ZnSO4, compared with DNTGFRII mice not given ZnSO4. The stimulatory effects of hypoxic exposure on pulmonary arterial cell proliferation and lung ECM proteins were abrogated in DNTGFRII mice given ZnSO4. These data support the conclusion that TGF- plays an important role in hypoxia-induced pulmonary vascular adaptation and IAD in the newborn animal model.
