Differential Expression of VEGF-Axxx Isoforms is Critical for Development of Pulmonary Fibrosis

Shaney Barratt, Thomas Blythe, Caroline E Jarrett, Khadija Ourradi, Golda Shelley-Fraser, Michael Day, Yan Qiu, Steven Harper, Toby Maher, Sebastian Oltean, Thomas Hames, Chris Scotton, Gavin Welsh, Dave O Bates, Ann Millar

Research output: Contribution to journalArticle (Academic Journal)peer-review

23 Citations (Scopus)


Rationale: Fibrosis following lung injury is related to poor outcome and Idiopathic Pulmonary Fibrosis (IPF) can be regarded as an exemplar. Vascular Endothelial Growth Factor-A (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-A165a, and VEGF-A165b a member of the inhibitory family. To-date there is no clear information on the role of VEGF in IPF.

Objectives: To establish VEGF isoform expression and functional effects in IPF.

Methods: We used tissue sections, plasma and lung fibroblasts from IPF patients and controls. In a bleomycin-induced lung fibrosis model we used wild type MMTV mice and a triple transgenic mouse SPC-rtTA+/-TetoCre+/-LoxP-VEGF-A+/+ to conditionally induce VEGF-A isoform deletion specifically in the ATII cells of adult mice.

Measurements and main Results: IPF and normal lung fibroblasts differentially expressed and responded to VEGF-A165a and VEGF-A165b, in terms of proliferation and matrix expression. Increased VEGF-A165b was detected in sera of progressing IPF patients. In a mouse model of pulmonary fibrosis alveolar type II cell (ATII) specific deficiency of VEGF-A or constitutive over-expression of VEGF-A165b inhibited the development of pulmonary fibrosis, as did treatment with intra-peritoneal delivery of VEGF-A165b 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-Axxxa to VEGF-Axxxb, are critical in development of pulmonary fibrosis and may be a paradigm for the regulation of tissue repair.
Original languageEnglish
Pages (from-to)479–493
Number of pages15
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number4
Early online date29 Jun 2017
Publication statusPublished - 15 Aug 2017


  • Vascular Endothelial Growth Factor ( VEGF)
  • Pulmonary Fibrosis
  • Animal Models of pulmonary fibrosis


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