VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats

• Published in: The Journal of clinical investigation 2009-05, Vol.119 (5), p.1298-1311
• Main Authors: Farkas, Laszlo, Farkas, Daniela, Ask, Kjetil, Möller, Antje, Gauldie, Jack, Margetts, Peter, Inman, Mark, Kolb, Martin
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Apoptosis; Apoptosis - drug effects; Biomedical research; Bronchoalveolar Lavage Fluid - chemistry; Care and treatment; Caspase 3 - metabolism; Disease Models, Animal; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Eye Proteins - genetics; Eye Proteins - metabolism; Female; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene Expression - genetics; Genetic aspects; Genetic Therapy; Health aspects; Humans; Hypertension, Pulmonary - etiology; Hypertension, Pulmonary - physiopathology; Hypertension, Pulmonary - therapy; Idiopathic Pulmonary Fibrosis - chemically induced; Idiopathic Pulmonary Fibrosis - complications; Idiopathic Pulmonary Fibrosis - metabolism; Idiopathic Pulmonary Fibrosis - pathology; Idiopathic Pulmonary Fibrosis - therapy; Immunohistochemistry; Lung - metabolism; Lung - pathology; Lung - physiopathology; Lungs; Medical prognosis; Microvessels - drug effects; Microvessels - pathology; Models, Biological; Nerve Growth Factors - genetics; Nerve Growth Factors - metabolism; Nitric Oxide Synthase Type III - genetics; Pathogenesis; Phosphorylation; Pulmonary arteries; Pulmonary Artery - metabolism; Pulmonary Artery - pathology; Pulmonary fibrosis; Pulmonary hypertension; Rats; Rats, Sprague-Dawley; Risk factors; Serpins - genetics; Serpins - metabolism; Serum Albumin - metabolism; Smad2 Protein - metabolism; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming Growth Factor beta1 - pharmacology; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor A - therapeutic use; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Veins & arteries
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI36136

Idiopathic pulmonary fibrosis (IPF) can lead to the development of secondary pulmonary hypertension (PH) and ultimately death. Despite this known association, the precise mechanism of disease remains unknown. Using a rat model of IPF, we explored the role of the proangiogenic and antiapoptotic growth factor VEGF in the vascular remodeling that underlies PH. In this model, adenoviral delivery of active TGF-beta1 induces pulmonary arterial remodeling, loss of the microvasculature in fibrotic areas, and increased pulmonary arterial pressure (PAP). Immunohistochemistry and mRNA analysis revealed decreased levels of VEGF and its receptor, which were inversely correlated with PAP and endothelial cell apoptosis in both the micro- and macrovasculature. Treatment of IPF rats with adenoviral delivery of VEGF resulted in reduced endothelial apoptosis, increased vascularization, and improved PAP due to reduced remodeling but worsened PF. These data show that experimental pulmonary fibrosis (PF) leads to loss of the microvasculature through increased apoptosis and to remodeling of the pulmonary arteries, with both processes resulting in PH. As administration of VEGF ameliorated the PH in this model but concomitantly aggravated the fibrogenic process, VEGF-based therapies should be used with caution.