Vascular Endothelial Growth Factor (VEGF) isoform expression and activity in human and murine lung injury
Author(s)
Type
Journal Article
Abstract
Background
The properties of vascular endothelial growth factor (VEGF) as a potent vascular permogen and mitogen have led to investigation of its potential role in lung injury. Alternate spliced VEGF transcript generates several isoforms with potentially differing functions. The purpose of this study was to determine VEGF isoform expression and source in normal and ARDS subjects and investigate the expression and regulation of VEGF isoforms by human alveolar type 2 (ATII) cells.
Methods
VEGF protein expression was assessed immunohistochemically in archival normal and ARDS human lung tissue. VEGF isoform mRNA expression was assessed in human and murine lung tissue. Purified ATII cells were cultured with proinflammatory cytokines prior to RNA extraction/cell supernatant sampling/proliferation assay.
Measurements and Main Results
VEGF was expressed on alveolar epithelium, vascular endothelium and alveolar macrophages in normal and ARDS human lung tissue. Increases in VEGF expression were detected in later ARDS in comparison to both normal subjects and early ARDS (p < 0.001). VEGF121, VEGF165 and VEGF189 isoform mRNA expression increased in later ARDS (p < 0.05). The ratio of soluble to cell-associated isoforms was lower in early ARDS than normal subjects and later ARDS and also in murine lung injury. ATII cells constitutionally produced VEGF165 and VEGF121 protein which was increased by LPS (p < 0.05). VEGF165 upregulated ATII cell proliferation (p < 0.001) that was inhibited by soluble VEGF receptor 1 (sflt) (p < 0.05).
Conclusion
These data demonstrate that changes in VEGF isoform expression occur in ARDS which may be related to their production by and mitogenic effect on ATII cells; with potentially significant clinical consequences.
The properties of vascular endothelial growth factor (VEGF) as a potent vascular permogen and mitogen have led to investigation of its potential role in lung injury. Alternate spliced VEGF transcript generates several isoforms with potentially differing functions. The purpose of this study was to determine VEGF isoform expression and source in normal and ARDS subjects and investigate the expression and regulation of VEGF isoforms by human alveolar type 2 (ATII) cells.
Methods
VEGF protein expression was assessed immunohistochemically in archival normal and ARDS human lung tissue. VEGF isoform mRNA expression was assessed in human and murine lung tissue. Purified ATII cells were cultured with proinflammatory cytokines prior to RNA extraction/cell supernatant sampling/proliferation assay.
Measurements and Main Results
VEGF was expressed on alveolar epithelium, vascular endothelium and alveolar macrophages in normal and ARDS human lung tissue. Increases in VEGF expression were detected in later ARDS in comparison to both normal subjects and early ARDS (p < 0.001). VEGF121, VEGF165 and VEGF189 isoform mRNA expression increased in later ARDS (p < 0.05). The ratio of soluble to cell-associated isoforms was lower in early ARDS than normal subjects and later ARDS and also in murine lung injury. ATII cells constitutionally produced VEGF165 and VEGF121 protein which was increased by LPS (p < 0.05). VEGF165 upregulated ATII cell proliferation (p < 0.001) that was inhibited by soluble VEGF receptor 1 (sflt) (p < 0.05).
Conclusion
These data demonstrate that changes in VEGF isoform expression occur in ARDS which may be related to their production by and mitogenic effect on ATII cells; with potentially significant clinical consequences.
Date Issued
2009-04-09
Date Acceptance
2009-04-09
Citation
Respiratory Research, 2009, 10
ISSN
1465-993X
Publisher
BioMed Central
Journal / Book Title
Respiratory Research
Volume
10
Copyright Statement
© Medford et al. 2009. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
License URL
Sponsor
Medical Research Council (MRC)
Grant Number
G0700926
Subjects
Science & Technology
Life Sciences & Biomedicine
Respiratory System
RESPIRATORY SYSTEM
RESPIRATORY-DISTRESS-SYNDROME
FACTOR MESSENGER-RNA
EPITHELIAL-CELLS
SPLICE VARIANTS
RECEPTORS
ARDS
PERMEABILITY
PROGRESS
TISSUE
GENE
Aged
Animals
Female
Gene Expression Regulation
Humans
Lung
Lung Injury
Male
Mice
Mice, Inbred C57BL
Protein Isoforms
Species Specificity
Tissue Distribution
Vascular Endothelial Growth Factor A
1102 Cardiovascular Medicine And Haematology
1103 Clinical Sciences
Publication Status
Published
Article Number
27