TY - JOUR
T1 - Effect of VEGF-A on expression of profibrotic growth factor and extracellular matrix genes in the retina
AU - Kuiper, Esther J.
AU - Hughes, John M.
AU - van Geest, Rob J.
AU - Vogels, Ilse M. C.
AU - Goldschmeding, Roel
AU - van Noorden, Cornelis J. F.
AU - Schlingemann, Reinier O.
AU - Klaassen, Ingeborg
PY - 2007
Y1 - 2007
N2 - PURPOSE. Vascular endothelial growth factor-A ( VEGF) causes increased vascular permeability and leukocyte adhesion in preclinical diabetic retinopathy ( PCDR). Another hallmark of PCDR is thickening of the capillary basement membrane ( BM). Recently, VEGF has been shown to induce expression of pro-fibrotic genes such as transforming growth factor ( TGF)-beta 1 and connective tissue growth factor ( CTGF or CCN2) in cultured endothelial cells. Moreover, neutralization of VEGF prevented BM thickening in diabetic mice in vivo. The authors hypothesize that VEGF directly contributes to BM thickening in the diabetic retina by inducing expression of profibrotic growth factors and extracellular matrix (ECM) components. METHODS. Transcription and protein levels of ECM-related genes were evaluated in the rat retina after intravitreal VEGF injection by real-time quantitative PCR, Western blot analysis, and immunohistochemistry. In addition, expression profiles of the same genes in response to VEGF stimulation were investigated in bovine retinal vascular cells in vitro. RESULTS. Intravitreal VEGF injection induced retinal transcription of CYR61 (CCN1), CTGF, TGF-beta 1, tissue inhibitor of metalloproteases ( TIMP)-1 and fibronectin, and protein expression of CYR61, CTGF, TGF-beta 1 and fibronectin. In bovine retinal endothelial cells and pericytes stimulated by VEGF in vitro, gene expression profiles were similar to those in the intact retina in vivo. CONCLUSIONS. VEGF induces profibrotic growth factors and extracellular matrix genes in the retina in vivo, as well as in cultured retinal vascular cells in vitro. The current findings have relevance for understanding the pathogenesis of preclinical DR, where early upregulation of VEGF may cause BM thickening by induction of ECM-related genes
AB - PURPOSE. Vascular endothelial growth factor-A ( VEGF) causes increased vascular permeability and leukocyte adhesion in preclinical diabetic retinopathy ( PCDR). Another hallmark of PCDR is thickening of the capillary basement membrane ( BM). Recently, VEGF has been shown to induce expression of pro-fibrotic genes such as transforming growth factor ( TGF)-beta 1 and connective tissue growth factor ( CTGF or CCN2) in cultured endothelial cells. Moreover, neutralization of VEGF prevented BM thickening in diabetic mice in vivo. The authors hypothesize that VEGF directly contributes to BM thickening in the diabetic retina by inducing expression of profibrotic growth factors and extracellular matrix (ECM) components. METHODS. Transcription and protein levels of ECM-related genes were evaluated in the rat retina after intravitreal VEGF injection by real-time quantitative PCR, Western blot analysis, and immunohistochemistry. In addition, expression profiles of the same genes in response to VEGF stimulation were investigated in bovine retinal vascular cells in vitro. RESULTS. Intravitreal VEGF injection induced retinal transcription of CYR61 (CCN1), CTGF, TGF-beta 1, tissue inhibitor of metalloproteases ( TIMP)-1 and fibronectin, and protein expression of CYR61, CTGF, TGF-beta 1 and fibronectin. In bovine retinal endothelial cells and pericytes stimulated by VEGF in vitro, gene expression profiles were similar to those in the intact retina in vivo. CONCLUSIONS. VEGF induces profibrotic growth factors and extracellular matrix genes in the retina in vivo, as well as in cultured retinal vascular cells in vitro. The current findings have relevance for understanding the pathogenesis of preclinical DR, where early upregulation of VEGF may cause BM thickening by induction of ECM-related genes
U2 - https://doi.org/10.1167/iovs.06-0804
DO - https://doi.org/10.1167/iovs.06-0804
M3 - Article
C2 - 17724216
SN - 0146-0404
VL - 48
SP - 4267
EP - 4276
JO - Investigative Ophthalmology & Visual Science
JF - Investigative Ophthalmology & Visual Science
IS - 9
ER -