TGF-beta 1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo

Members of the transforming growth factor beta (TGF-beta) family of polypep tides have been implicated in morphogenesis and differentiation in numerous tissues, including the lung. In order to further define effects of TGF-bet a signaling in lung morphogenesis, a constitutively active form of TGF-beta 1 was expressed in respiratory epithelial cells of the fetal mouse lung in vivo. Expression of TGF-beta1 arrested lung morphogenesis in the pseudoglan dular stage of development, inhibiting synthesis of differentiation-depende nt proteins, SP-B, SP-C, and CCSP, and maintaining embryonic patterns of st aining for thyroid transcription factor-1 (TTF-1) and hepatocyte nuclear fa ctor-3 beta (HNF-3 beta), The pulmonary mesenchyme was thickened and vascul ar density was increased by TGF-beta1, TGF-beta1 decreased expression of va scular endothelial growth factor-A (VEGF-A) mRNA and protein, and the abund ance of Flk-1 mRNA in the lung mesenchyme. Distribution of platelet-endothe lial cell adhesion molecule (PECAM)-1, a marker of pulmonary blood vessels, was altered, and ultrastructural studies demonstrated that TGF-beta1 inhib ited vascular development in the fetal lung. TGF-beta1 perturbed both epith elial cell differentiation and formation of the pulmonary vasculature, supp orting the concept that precise control of signaling via the TGF-beta recep tor pathway is critical for normal lung morphogenesis, (C) 2001 Wiley-Liss, Inc.