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Effect of low VEGF on lung development and function

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Abstract

Vascular endothelial growth factor (VEGF) is important for lung development and function but ideal mouse models are limited to decipher the quantitative relationship between VEGF expression levels and its proper development and pathogenesis. Human SPC promoter has been used to faithfully express genes or cDNAs in the pulmonary epithelium in many transgenic mouse models. In the study, a mouse model of lung-specific and reversible VEGF repression (hspc-rtTRtg/+/VegftetO/tetO) was generated. Human SPC promoter was used to drive lung-specific rtTR expression, a cDNA coding for doxycycline-regulated transcription repression protein. By crossing with VegftetO/tetO mice, that has tetracycline operator sequences insertion in 5′-UTR region, it allows us to reversibly inhibit lung VEGF transcription from its endogenous level through doxycycline food, water or injection. The tissue-specific inhibition of VEGF is used to mimic abnormal expression levels of VEGF in lung. Reduced VEGF expression in lung is confirmed by quantitative real time PCR and immunoblotting. Lung development and structure was analyzed by histology analysis and found significantly affected under low VEGF. The pulmonary epithelium and alveolarization are found abnormal with swelling alveolar septum and enlargement of air space. Genome-wide gene expression analysis identified that immune activities are involved in the VEGF-regulated lung functions. The transgenic mouse model can be used to mimic human pulmonary diseases. The mouse model confirms the important regulatory roles of epithelial expressed VEGF in lung development and function. This mouse model is valuable for studying VEGF-regulated lung development, pathogenesis and drug screening under low VEGF expression.

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Abbreviations

VEGF:

Vascular endothelial growth factor

VEGFA:

Vascular endothelial growth factor A

VEGFR1:

Vascular endothelial growth factor receptor1

VEGFR2:

Vascular endothelial growth factor receptor2

Flt-1:

Fms like tryosyl kinase-1

Flk-1/KDR:

Fetal liver kinase-1/kinase domain-containing receptor

TetO:

Tetracycline operator

TetR:

Tetracycline repressor

Dox:

Doxycycline

HSP-C:

Human surfactant protein C

CD5L:

Cyclin-dependent kinase-like 5

WDR49:

WD Repeat Domain 49

LIPF:

Lipase F, gastric type

CNTN1:

Contactin 1

Mup10:

Major urinary protein 10

KCNH4:

Potassium Voltage-Gated Channel Subfamily H member 4

SOX10:

SRY-box transcription factor 10

Gbp2b:

Guanylate binding protein 2b

ARSI:

Arylsulfatase family member I

Fam2051:

Family with sequence similarity 205 Member A)

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Acknowledgments

Authors would like to thank Ms. Xiulu Lu and Huiyan Wu for microinjection and mouse colony management.

Funding

This study is supported by National Natural Science Foundation of China (81270953), the Natural Science Foundation of Jilin Province (20160101344JC) and Science and Technology Project of Jilin Provincial Education Department (JJKH20180023KJ).

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    Authors and Affiliations

    1. Transgenic Research Center, Northeast Normal University, Changchun, Jilin, China

      May Zun Zaw Myint, Jia Jia, Salah Adlat, Zin Mar Oo, Hsu Htoo, Farooq Hayel, Yang Chen, Fatoumata Binta Bah, Rajiv Kumar Sah, Noor Bahadar, Xuechao Feng & Yaowu Zheng

    2. Key Laboratory of Molecular Epigenetics of Ministry of Education, School of Life Sciences, Northeast Normal University, Changchun, 130024, Jilin, China

      Luqing Zhang, Xuechao Feng & Yaowu Zheng

    3. Cardiovascular Research Institute, University of California, San Francisco, CA, USA

      Luqing Zhang

    4. Jilin Province Key Laboratory on Chemistry and Biology of Natural Drugs in Changbai Mountain, School of Life Sciences, Northeast Normal University, Changchun, 130024, Jilin Province, China

      Mi Kaythi Chan

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    1. May Zun Zaw Myint
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    Contributions

    Conceptualization: YZ; Data curation: MZZM, JJ, ZMO, SA; Formal analysis: MZZM, RKS, SA; Funding acquisition: XF, and YZ; Investigation; MZZM, JJ, YC, SA, ZMO, FH; Methodology: MZZM, JJ, YC, YZ; Project administration: YZ; Resources: XF, and YZ; Software: MZZM, RKS; Supervision: LZ, XF, and YZ; Validation: MZZM, JJ, YZ; Visualization: HH, FH, NB, MKC; Writing—original draft preparation: MZZM, JJ; Writing—review and editing: LZ, XF, and YZ.

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    Correspondence to Luqing Zhang, Xuechao Feng or Yaowu Zheng.

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    May Zun Zaw Myint and Jia Jia have contributed equally to this work.

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    Myint, M.Z.Z., Jia, J., Adlat, S. et al. Effect of low VEGF on lung development and function. Transgenic Res 30, 35–50 (2021). https://doi.org/10.1007/s11248-020-00223-w

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