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 7

Proposed mechanism of SM regulation by endogenous RA.

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Proposed mechanism of SM regulation by endogenous RA. During branching o...
During branching of the developing airways, a program of differentiation of SM takes place in the distal mesenchyme at the newly formed stalks of the lung buds (white circled area). RA signaling is activated in these areas, as evidenced by locally enriched RARElacZ expression (inset) at these sites. Endogenous RA regulates this SM program, restricting SM gene expression and preventing excessive formation of SM while airways are branching. As new generations of airways arise, the process is reiterated, and the RA restriction of the SM program becomes less crucial proximally (left panel, dashed yellow lines). RA fine-tunes the SM gene expression program, likely by inhibiting the expression of a key activator of SM transcription (in green) or by inducing the expression of the transcriptional repressor (in blue), ultimately resulting in the downregulation of SM gene expression.