Shaney L. Barratt
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.
Michael J. Day
Toby M. Maher
Thomas J. Hames
Chris J. Scotton
Gavin I. Welsh
DAVID BATES David.Bates@nottingham.ac.uk
Professor of Oncology
Ann B. Millar
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.
To establish VEGF-A isoform expression and functional effects in IPF.
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.
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.
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|
|Publisher||American Thoracic Society|
|Peer Reviewed||Peer Reviewed|
|Copyright Statement||Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf|
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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