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Differential expression of VEGF-Axxx isoforms is critical for development of pulmonary fibrosis

Barratt, Shaney L.; Blythe, Thomas; Jarrett, Caroline; Ourradi, Khadija; Shelley-Fraser, Golda; Day, Michael J.; Qiu, Yan; Harper, Steve; Maher, Toby M.; Oltean, Sebastian; Hames, Thomas J.; Scotton, Chris J.; Welsh, Gavin I.; Bates, David O.; Millar, Ann B.

Authors

Shaney L. Barratt

Thomas Blythe

Caroline Jarrett

Khadija Ourradi

Golda Shelley-Fraser

Michael J. Day

Yan Qiu

Steve Harper

Toby M. Maher

Sebastian Oltean

Thomas J. Hames

Chris J. Scotton

Gavin I. Welsh

Ann B. Millar



Abstract

RATIONALE

Fibrosis after lung injury is related to poor outcome, and idiopathic pulmonary fibrosis (IPF) can be regarded as an exemplar. Vascular endothelial growth factor (VEGF)-A has been implicated in this context, but there are conflicting reports as to whether it is a contributory or protective factor. Differential splicing of the VEGF-A gene produces multiple functional isoforms including VEGF-Aa and VEGF-Ab, a member of the inhibitory family. To date there is no clear information on the role of VEGF-A in IPF.

OBJECTIVES

To establish VEGF-A isoform expression and functional effects in IPF.

METHODS

We used tissue sections, plasma, and lung fibroblasts from patients with IPF and control subjects. In a bleomycin-induced lung fibrosis model we used wild-type MMTV mice and a triple transgenic mouse SPC-rtTATetoCreLoxP-VEGF-Ato conditionally induce VEGF-A isoform deletion specifically in the alveolar type II (ATII) cells of adult mice.

MEASUREMENTS AND MAIN RESULTS

IPF and normal lung fibroblasts differentially expressed and responded to VEGF-Aa and VEGF-Ab in terms of proliferation and matrix expression. Increased VEGF-Ab was detected in plasma of progressing patients with IPF. In a mouse model of pulmonary fibrosis, ATII-specific deficiency of VEGF-A or constitutive overexpression of VEGF-Ab inhibited the development of pulmonary fibrosis, as did treatment with intraperitoneal delivery of VEGF-Ab to wild-type mice.

CONCLUSIONS

These results indicate that changes in the bioavailability of VEGF-A sourced from ATII cells, namely the ratio of VEGF-Aa to VEGF-Ab, are critical in development of pulmonary fibrosis and may be a paradigm for the regulation of tissue repair.

Citation

Barratt, S. L., Blythe, T., Jarrett, C., Ourradi, K., Shelley-Fraser, G., Day, M. J., …Millar, A. B. (2017). Differential expression of VEGF-Axxx isoforms is critical for development of pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine, 196(4), https://doi.org/10.1164/rccm.201603-0568OC

Journal Article Type Article
Acceptance Date Jul 17, 2017
Publication Date Aug 15, 2017
Deposit Date Mar 5, 2018
Publicly Available Date Aug 16, 2018
Journal American Journal of Respiratory and Critical Care Medicine
Print ISSN 1073-449X
Electronic ISSN 1535-4970
Publisher American Thoracic Society
Peer Reviewed Peer Reviewed
Volume 196
Issue 4
DOI https://doi.org/10.1164/rccm.201603-0568OC
Public URL http://eprints.nottingham.ac.uk/id/eprint/50180
Publisher URL https://www.atsjournals.org/doi/10.1164/rccm.201603-0568OC
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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