Prenatal retinoid deficiency leads to airway hyperresponsiveness in adult mice
Felicia Chen, … , Loredana Quadro, Wellington V. Cardoso
Felicia Chen, … , Loredana Quadro, Wellington V. Cardoso
Published January 9, 2014
Citation Information: J Clin Invest. 2014;124(2):801-811. https://doi.org/10.1172/JCI70291.
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Research Article Pulmonology

Prenatal retinoid deficiency leads to airway hyperresponsiveness in adult mice

Abstract

There is increasing evidence that vitamin A deficiency in utero correlates with abnormal airway smooth muscle (SM) function in postnatal life. The bioactive vitamin A metabolite retinoic acid (RA) is essential for formation of the lung primordium; however, little is known about the impact of early fetal RA deficiency on postnatal lung structure and function. Here, we provide evidence that during murine lung development, endogenous RA has a key role in restricting the airway SM differentiation program during airway formation. Using murine models of pharmacological, genetic, and dietary vitamin A/RA deficiency, we found that disruption of RA signaling during embryonic development consistently resulted in an altered airway SM phenotype with markedly increased expression of SM markers. The aberrant phenotype persisted postnatally regardless of the adult vitamin A status and manifested as structural changes in the bronchial SM and hyperresponsiveness of the airway without evidence of inflammation. Our data reveal a role for endogenous RA signaling in restricting SM differentiation and preventing precocious and excessive SM differentiation when airways are forming.

Authors

Felicia Chen, Hector Marquez, Youn-Kyung Kim, Jun Qian, Fengzhi Shao, Alan Fine, William W. Cruikshank, Loredana Quadro, Wellington V. Cardoso

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Figure 2

RA is active at sites of SM differentiation in developing distal airways.

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RA is active at sites of SM differentiation in developing distal airways...
(A–C) X-gal staining of E11.5 (A) and E13.5 (B and C) RARElacZ lungs; mesenchymal signals were prominent in the distal lung (di, circled). (C) Cross section of E13.5 lung. (D–H) X-gal staining of cultured lung (48 and 72 hours). Strong local RA activity in the mesenchyme at the stalks of forming buds was seen at 48 hours (D and F, arrowheads; circled areas). At 72 hours, the pattern was more prominent, with multiple areas of RARElacZ labeling the mesenchyme associated with newly formed distal airways (E and G). Signals declined or were undetectable in more proximal branches, although they were present in trachea and main bronchi, being abolished by BMS treatment (H). Myocardin (Myocd) signals (ISH) were enriched in areas of strong RA activity (I, F, and G, arrowheads). (J–L) Lung culture from Acta2-GFP;RARElacZ mice showing GFP signals associated with airway SM (J). SM cells isolated by FACS expressed RA pathway components and activated RA signaling (K and L, PCR; negative controls: cells from Acta-GFP, non-RARElacZ, and MLE15 line). Scale bars: 55 μm (D) and 45 μm (I). n = 3–5 per condition for all experiments.