title: VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats.
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.
authors.affiliation: Department of Medicine, McMaster University, Firestone Institute for Respiratory Health and St. Joseph's Healthcare, Hamilton, Ontario, Canada.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Farkas
authors.forename: Daniela
authors.initials: D
authors.lastname: Farkas
authors.forename: Kjetil
authors.initials: K
authors.lastname: Ask
authors.forename: Antje
authors.initials: A
authors.lastname: Möller
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
authors.forename: Peter
authors.initials: P
authors.lastname: Margetts
authors.forename: Mark
authors.initials: M
authors.lastname: Inman
authors.forename: Martin
authors.initials: M
authors.lastname: Kolb
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D015316:Genetic Therapy; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D008954:Models, Biological; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D010766:Phosphorylation; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015843:Serpins / Q000235:genetics / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D053148:Caspase 3; D005136:Eye Proteins; D009414:Nerve Growth Factors; D052250:Nitric Oxide Synthase Type III; D015843:Serpins; D012709:Serum Albumin; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099174:Pigment Epithelium-Derived Factor; C497784:Smad2 protein, rat; C496316:Nos3 protein, rat