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 5

Consequences of prenatal VAD in the SM phenotype of the adult lung.

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Consequences of prenatal VAD in the SM phenotype of the adult lung. (A) ...
(A) Diagram of experimental design. (B) HPLC measurements of retinoids in the lung homogenates of adult mice: no difference between VAS and VAD groups, but significantly lower levels in DKO compared with WT mice. (C–E) Significantly lower levels of RARElacZ (C) correlating with Tagln and Myh11 upregulation (D) by qPCR in DKO lungs compared with WT. (E) Significant increase in SM22α, SMMHC2, and pMYL2/tMYL2 ratio levels in lung homogenates of WT-VAD, DKO-VAS, and DKO-VAD mice compared with those in WT-VAS lung homogenates by Western blot analysis. IHC of SM markers in adult proximal airways (F–K: Acta2; M–N: Sm22α) showing increased expression in VAD groups (double arrows). Quantitative analysis of Acta2 (L) and Sm22α (O) IHC: signal intensity, relative volume of staining per SA, and relative number of labeled cells per SA in proximal airways (large and medium size, see Methods) suggest a significant increase in SM mass in VAD lungs relative to VAS lungs. Data represent the mean ± SEM, n = 3 per condition. *P < 0.05 compared with WT-VAS; #P < 0.05 compared with DKO-VAS. Scale bars: 30 μm (I) and 20 μm (M). AW, airway.