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

Barratt, Shaney L. and Blythe, Thomas and Jarrett, Caroline and Ourradi, Khadija and Shelley-Fraser, Golda and Day, Michael J. and Qiu, Yan and Harper, Steve and Maher, Toby M. and Oltean, Sebastian and Hames, Thomas J. and Scotton, Chris J. and Welsh, Gavin I. and Bates, David O. and Millar, Ann 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). pp. 479-493. ISSN 1535-4970

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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.


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.

Item Type: Article
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Cancer and Stem Cells
Identification Number: 10.1164/rccm.201603-0568OC
Depositing User: Bates, David
Date Deposited: 05 Mar 2018 13:22
Last Modified: 05 Mar 2018 21:06
URI: http://eprints.nottingham.ac.uk/id/eprint/50180

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