TGF-beta1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo.
Members of the transforming growth factor beta (TGF-beta) family of polypeptides have been implicated in morphogenesis and differentiation in numerous tissues, including the lung. In order to further define effects of TGF-beta signaling in lung morphogenesis, a constitutively active form of TGF-beta1 was expressed in respiratory epithelial cells of the fetal mouse lung in vivo. Expression of TGF-beta1 arrested lung morphogenesis in the pseudoglandular stage of development, inhibiting synthesis of differentiation-dependent proteins, SP-B, SP-C, and CCSP, and maintaining embryonic patterns of staining for thyroid transcription factor-1 (TTF-1) and hepatocyte nuclear factor-3beta (HNF-3beta). The pulmonary mesenchyme was thickened and vascular density was increased by TGF-beta1. TGF-beta1 decreased expression of vascular endothelial growth factor-A (VEGF-A) mRNA and protein, and the abundance of Flk-1 mRNA in the lung mesenchyme. Distribution of platelet-endothelial cell adhesion molecule (PECAM)-1, a marker of pulmonary blood vessels, was altered, and ultrastructural studies demonstrated that TGF-beta1 inhibited vascular development in the fetal lung. TGF-beta1 perturbed both epithelial cell differentiation and formation of the pulmonary vasculature, supporting the concept that precise control of signaling via the TGF-beta receptor pathway is critical for normal lung morphogenesis.
Zeng
X
X
Children's Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, Ohio 45229-3039, USA.
Gray
M
M
Stahlman
M T
MT
Whitsett
J A
JA
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation; D016228:Endothelial Growth Factors / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology; D008168:Lung / Q000098:blood supply* / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis; D011510:Proteolipids / Q000235:genetics / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A
D016228:Endothelial Growth Factors; D011510:Proteolipids; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D001973:Bromodeoxyuridine