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.

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: https://nottingham-repository.worktribe.com/output/877875
• Publisher URL: https://www.atsjournals.org/doi/10.1164/rccm.201603-0568OC