Sequestration of Vascular Endothelial Growth Factor (VEGF) Induces Late Restrictive Lung Disease

RATIONALE: Neonatal respiratory distress syndrome is a restrictive lung disease characterized by surfactant deficiency. Decreased vascular endothelial growth factor (VEGF), which demonstrates important roles in angiogenesis and vasculogenesis, has been implicated in the pathogenesis of restrictive l...

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Autores principales: Wieck, Minna M., Spurrier, Ryan G., Levin, Daniel E., Mojica, Salvador Garcia, Hiatt, Michael J., Reddy, Raghava, Hou, Xiaogang, Navarro, Sonia, Lee, Jooeun, Lundin, Amber, Driscoll, Barbara, Grikscheit, Tracy C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749176/
https://www.ncbi.nlm.nih.gov/pubmed/26863115
http://dx.doi.org/10.1371/journal.pone.0148323
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author Wieck, Minna M.
Spurrier, Ryan G.
Levin, Daniel E.
Mojica, Salvador Garcia
Hiatt, Michael J.
Reddy, Raghava
Hou, Xiaogang
Navarro, Sonia
Lee, Jooeun
Lundin, Amber
Driscoll, Barbara
Grikscheit, Tracy C.
author_facet Wieck, Minna M.
Spurrier, Ryan G.
Levin, Daniel E.
Mojica, Salvador Garcia
Hiatt, Michael J.
Reddy, Raghava
Hou, Xiaogang
Navarro, Sonia
Lee, Jooeun
Lundin, Amber
Driscoll, Barbara
Grikscheit, Tracy C.
author_sort Wieck, Minna M.
collection PubMed
description RATIONALE: Neonatal respiratory distress syndrome is a restrictive lung disease characterized by surfactant deficiency. Decreased vascular endothelial growth factor (VEGF), which demonstrates important roles in angiogenesis and vasculogenesis, has been implicated in the pathogenesis of restrictive lung diseases. Current animal models investigating VEGF in the etiology and outcomes of RDS require premature delivery, hypoxia, anatomically or temporally limited inhibition, or other supplemental interventions. Consequently, little is known about the isolated effects of chronic VEGF inhibition, started at birth, on subsequent developing lung structure and function. OBJECTIVES: To determine whether inducible, mesenchyme-specific VEGF inhibition in the neonatal mouse lung results in long-term modulation of AECII and whole lung function. METHODS: Triple transgenic mice expressing the soluble VEGF receptor sFlt-1 specifically in the mesenchyme (Dermo-1/rtTA/sFlt-1) were generated and compared to littermate controls at 3 months to determine the impact of neonatal downregulation of mesenchymal VEGF expression on lung structure, cell composition and function. Reduced tissue VEGF bioavailability has previously been demonstrated with this model. MEASUREMENTS AND MAIN RESULTS: Triple transgenic mice demonstrated restrictive lung pathology. No differences in gross vascular development or protein levels of vascular endothelial markers was noted, but there was a significant decrease in perivascular smooth muscle and type I collagen. Mutants had decreased expression levels of surfactant protein C and hypoxia inducible factor 1-alpha without a difference in number of type II pneumocytes. CONCLUSIONS: These data show that mesenchyme-specific inhibition of VEGF in neonatal mice results in late restrictive disease, making this transgenic mouse a novel model for future investigations on the consequences of neonatal RDS and potential interventions.
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spelling pubmed-47491762016-02-26 Sequestration of Vascular Endothelial Growth Factor (VEGF) Induces Late Restrictive Lung Disease Wieck, Minna M. Spurrier, Ryan G. Levin, Daniel E. Mojica, Salvador Garcia Hiatt, Michael J. Reddy, Raghava Hou, Xiaogang Navarro, Sonia Lee, Jooeun Lundin, Amber Driscoll, Barbara Grikscheit, Tracy C. PLoS One Research Article RATIONALE: Neonatal respiratory distress syndrome is a restrictive lung disease characterized by surfactant deficiency. Decreased vascular endothelial growth factor (VEGF), which demonstrates important roles in angiogenesis and vasculogenesis, has been implicated in the pathogenesis of restrictive lung diseases. Current animal models investigating VEGF in the etiology and outcomes of RDS require premature delivery, hypoxia, anatomically or temporally limited inhibition, or other supplemental interventions. Consequently, little is known about the isolated effects of chronic VEGF inhibition, started at birth, on subsequent developing lung structure and function. OBJECTIVES: To determine whether inducible, mesenchyme-specific VEGF inhibition in the neonatal mouse lung results in long-term modulation of AECII and whole lung function. METHODS: Triple transgenic mice expressing the soluble VEGF receptor sFlt-1 specifically in the mesenchyme (Dermo-1/rtTA/sFlt-1) were generated and compared to littermate controls at 3 months to determine the impact of neonatal downregulation of mesenchymal VEGF expression on lung structure, cell composition and function. Reduced tissue VEGF bioavailability has previously been demonstrated with this model. MEASUREMENTS AND MAIN RESULTS: Triple transgenic mice demonstrated restrictive lung pathology. No differences in gross vascular development or protein levels of vascular endothelial markers was noted, but there was a significant decrease in perivascular smooth muscle and type I collagen. Mutants had decreased expression levels of surfactant protein C and hypoxia inducible factor 1-alpha without a difference in number of type II pneumocytes. CONCLUSIONS: These data show that mesenchyme-specific inhibition of VEGF in neonatal mice results in late restrictive disease, making this transgenic mouse a novel model for future investigations on the consequences of neonatal RDS and potential interventions. Public Library of Science 2016-02-10 /pmc/articles/PMC4749176/ /pubmed/26863115 http://dx.doi.org/10.1371/journal.pone.0148323 Text en © 2016 Wieck et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Wieck, Minna M.
Spurrier, Ryan G.
Levin, Daniel E.
Mojica, Salvador Garcia
Hiatt, Michael J.
Reddy, Raghava
Hou, Xiaogang
Navarro, Sonia
Lee, Jooeun
Lundin, Amber
Driscoll, Barbara
Grikscheit, Tracy C.
Sequestration of Vascular Endothelial Growth Factor (VEGF) Induces Late Restrictive Lung Disease
title Sequestration of Vascular Endothelial Growth Factor (VEGF) Induces Late Restrictive Lung Disease
title_full Sequestration of Vascular Endothelial Growth Factor (VEGF) Induces Late Restrictive Lung Disease
title_fullStr Sequestration of Vascular Endothelial Growth Factor (VEGF) Induces Late Restrictive Lung Disease
title_full_unstemmed Sequestration of Vascular Endothelial Growth Factor (VEGF) Induces Late Restrictive Lung Disease
title_short Sequestration of Vascular Endothelial Growth Factor (VEGF) Induces Late Restrictive Lung Disease
title_sort sequestration of vascular endothelial growth factor (vegf) induces late restrictive lung disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749176/
https://www.ncbi.nlm.nih.gov/pubmed/26863115
http://dx.doi.org/10.1371/journal.pone.0148323
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