Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects*
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Bronchoalveolar Lavage Fluid / chemistry
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Caspase 3 / metabolism
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Disease Models, Animal
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Endothelial Cells / cytology
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Endothelial Cells / drug effects*
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Endothelial Cells / metabolism
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Eye Proteins / genetics
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Eye Proteins / metabolism
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Female
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Gene Expression / genetics
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Genetic Therapy
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Humans
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Hypertension, Pulmonary / etiology
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Hypertension, Pulmonary / physiopathology
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Hypertension, Pulmonary / therapy*
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Idiopathic Pulmonary Fibrosis / chemically induced
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Idiopathic Pulmonary Fibrosis / complications
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Idiopathic Pulmonary Fibrosis / metabolism
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Idiopathic Pulmonary Fibrosis / pathology
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Idiopathic Pulmonary Fibrosis / therapy*
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Lung / metabolism
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Lung / pathology
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Lung / physiopathology
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Microvessels / drug effects
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Microvessels / pathology
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Models, Biological
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Nerve Growth Factors / genetics
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Nerve Growth Factors / metabolism
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Nitric Oxide Synthase Type III / genetics
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Phosphorylation
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Pulmonary Artery / metabolism
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Pulmonary Artery / pathology
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Rats
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Rats, Sprague-Dawley
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Serpins / genetics
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Serpins / metabolism
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Serum Albumin / metabolism
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Smad2 Protein / metabolism
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Transforming Growth Factor beta1 / genetics
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Transforming Growth Factor beta1 / metabolism
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Transforming Growth Factor beta1 / pharmacology
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Vascular Endothelial Growth Factor A / metabolism
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Vascular Endothelial Growth Factor A / pharmacology
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Vascular Endothelial Growth Factor A / therapeutic use*
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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Eye Proteins
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Nerve Growth Factors
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Serpins
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Serum Albumin
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Smad2 Protein
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Smad2 protein, rat
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Transforming Growth Factor beta1
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Vascular Endothelial Growth Factor A
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pigment epithelium-derived factor
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Nitric Oxide Synthase Type III
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Nos3 protein, rat
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Vascular Endothelial Growth Factor Receptor-2
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Caspase 3