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

Abstract

Members of the transforming growth factor ␤ (TGF-␤) family of polypeptides have been implicated in morphogenesis and differentiation in numerous tissues, including the lung. In order to further define effects of TGF-␤ signaling in lung morphogenesis, a constitutively active form of TGF-␤1 was expressed in respiratory epithelial cells of the fetal mouse lung in vivo. Expression of TGF-␤1 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-3␤ (HNF-3␤). The pulmonary mesenchyme was thickened and vascular density was increased by TGF-␤1. TGF-␤1 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-␤1 inhibited vascular development in the fetal lung. TGF-␤1 perturbed both epithelial cell differentiation and formation of the pulmonary vasculature, supporting the concept that precise control of signaling via the TGF-␤ receptor pathway is critical for normal lung morphogenesis.

Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice

“…The pattern of expression is most prominent in the lung peripheral epithelium, consistent with previous published studies of transgenic mice bearing the SP-C promoter constructs (Glasser et al, 1991;Wert et al, 1993;Zhou et al, 1997;Zeng et al, 2001). …”

Mechanisms of Lung Development: Contribution to Adult Lung Disease and Relevance to Chronic Obstructive Pulmonary Disease

“…Selective blockade of endogenous TGF-b signaling in embryonic lung mesenchymal cells results in retarded lung branching after midgestation, whereas abrogation of epithelial cell-specific TGF-b signaling causes mild abnormality in postnatal lung alveolization, but does not appear to have a significant impact on prenatal lung development (73). However, over-expression of TGF-b1 in the embryonic lung epithelium also results in the arrest of lung growth and epithelial cell differentiation and in inhibition of pulmonary vasculogenesis (74,75). Thus, appropriate TGF-b signaling activity is essential for normal lung development.…”

Matrix GLA Protein Stimulates VEGF Expression through Increased Transforming Growth Factor-β1 Activity in Endothelial Cells

“…TGF-␤ and VEGF are both involved in the development and maintenance of lungs (10,60), where correct spatial and timely expression of TGF-␤, TGF-␤ receptors, and VEGF is crucial for morphogenesis. For instance, constitutively active TGF-␤1 perturbs epithelial cell differentiation and formation of pulmonary vasculature (61), and misexpressed VEGF increases pulmonary vasculature but disrupts branching in developing respiratory epithelium (62).…”