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Publication - Professor Ann Millar

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


    Barratt, S, Blythe, T, Jarrett, CE, Ourradi, K, Shelley-Fraser, G, Day, M, Qiu, Y, Harper, S, Maher, T, Oltean, S, Hames, T, Scotton, C, Welsh, G, Bates, DO & Millar, A, 2017, ‘Differential Expression of VEGF-Axxx Isoforms is Critical for Development of Pulmonary Fibrosis’. American Journal of Respiratory and Critical Care Medicine, vol 196., pp. 479?493


    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.

    Full details in the University publications repository