TGF‐β1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo

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Abstract
Members of the transforming growth factor β (TGF‐β) family of polypeptides have been implicated in morphogenesis and differentiation in numerous tissues, including the lung. In order to further define effects of TGF‐β signaling in lung morphogenesis, a constitutively active form of TGF‐β1 was expressed in respiratory epithelial cells of the fetal mouse lung in vivo. Expression of TGF‐β1 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‐3β (HNF‐3β). The pulmonary mesenchyme was thickened and vascular density was increased by TGF‐β1. TGF‐β1 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‐β1 inhibited vascular development in the fetal lung. TGF‐β1 perturbed both epithelial cell differentiation and formation of the pulmonary vasculature, supporting the concept that precise control of signaling via the TGF‐β receptor pathway is critical for normal lung morphogenesis.

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