Differential Expression of VEGF-Axxx Isoforms Is Critical for Development of Pulmonary Fibrosis
SL Barratt, T Blythe, C Jarrett, K Ourradi… - American journal of …, 2017 - atsjournals.org
SL Barratt, T Blythe, C Jarrett, K Ourradi, G Shelley-Fraser, MJ Day, Y Qiu, S Harper…
American journal of respiratory and critical care medicine, 2017•atsjournals.orgRationale: 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-A165a and VEGF-A165b, a member of the inhibitory
family. To date there is no clear information on the role of VEGF-A in IPF. Objectives: To …
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-A165a and VEGF-A165b, a member of the inhibitory
family. To date there is no clear information on the role of VEGF-A in IPF. Objectives: To …
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-A165a and VEGF-A165b, 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-rtTA+/−TetoCre+/−LoxP-VEGF-A+/+ to 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-A165a and VEGF-A165b in terms of proliferation and matrix expression. Increased VEGF-A165b 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-A165b inhibited the development of pulmonary fibrosis, as did treatment with intraperitoneal 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.
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