Differential expression of VEGF-Axxx isoforms is critical for development of pulmonary fibrosis
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 protect...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Published: |
American Thoracic Society
2017
|
| Online Access: | https://eprints.nottingham.ac.uk/50180/ |
| _version_ | 1848798177198604288 |
|---|---|
| author | 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. |
| author_facet | 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. |
| author_sort | Barratt, Shaney L. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T20:15:37Z |
| format | Article |
| id | nottingham-50180 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:15:37Z |
| publishDate | 2017 |
| publisher | American Thoracic Society |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-501802020-05-04T19:00:50Z https://eprints.nottingham.ac.uk/50180/ 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. 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. American Thoracic Society 2017-08-15 Article PeerReviewed 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. 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 https://www.atsjournals.org/doi/10.1164/rccm.201603-0568OC doi:10.1164/rccm.201603-0568OC doi:10.1164/rccm.201603-0568OC |
| spellingShingle | 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. Differential expression of VEGF-Axxx isoforms is critical for development of pulmonary fibrosis |
| title | Differential expression of VEGF-Axxx isoforms is critical for development of pulmonary fibrosis |
| title_full | Differential expression of VEGF-Axxx isoforms is critical for development of pulmonary fibrosis |
| title_fullStr | Differential expression of VEGF-Axxx isoforms is critical for development of pulmonary fibrosis |
| title_full_unstemmed | Differential expression of VEGF-Axxx isoforms is critical for development of pulmonary fibrosis |
| title_short | Differential expression of VEGF-Axxx isoforms is critical for development of pulmonary fibrosis |
| title_sort | differential expression of vegf-axxx isoforms is critical for development of pulmonary fibrosis |
| url | https://eprints.nottingham.ac.uk/50180/ https://eprints.nottingham.ac.uk/50180/ https://eprints.nottingham.ac.uk/50180/ |