Differential Expression of VEGF-A xxx Isoforms Is Critical for Development of Pulmonary Fibrosis

• Published in: American journal of respiratory and critical care medicine 2017-08, Vol.196 (4), p.479-493
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; Gene Expression - genetics; Humans; Lung - physiopathology; Mice; Mice, Inbred C57BL; Protein Isoforms; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - physiopathology; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201603-0568OC

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-A a and VEGF-A b, 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-rtTA TetoCre LoxP-VEGF-A to 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-A a and VEGF-A b in terms of proliferation and matrix expression. Increased VEGF-A b 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-A b inhibited the development of pulmonary fibrosis, as did treatment with intraperitoneal delivery of VEGF-A b to wild-type mice. These results indicate that changes in the bioavailability of VEGF-A sourced from ATII cells, namely the ratio of VEGF-A a to VEGF-A b, are critical in development of pulmonary fibrosis and may be a paradigm for the regulation of tissue repair.