Over-expression of BMP4 inhibits experimental choroidal neovascularization by modulating VEGF and MMP-9 |
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Authors: | Xu Jing Zhu Danhong Sonoda Shozo He Shikun Spee Christine Ryan Stephen J Hinton David R |
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Institution: | (1) Department of Ophthalmology, Keck School of Medicine, The University of Southern California, Los Angeles, CA, USA;(2) The Doheny Eye Institute, Los Angeles, CA, USA;(3) Department of Pathology, Keck School of Medicine, The University of Southern California, 2011 Zonal Ave., HMR 209, Los Angeles, CA 90089, USA;(4) Department of Ophthalmology, Kagoshima University, Kagoshima, Japan; |
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Abstract: | Bone morphorgenetic protein (BMP)-4 has been shown to play a pivotal role in eye development; however, its role in mature
retina or ocular angiogenic diseases is unclear. Activating downstream Smad signaling, BMP4 can be either pro-angiogenic or
anti-angiogenic, depending on the context of cell types and associated microenvironment. In this study, we generated transgenic
mice over-expressing BMP4 in retinal pigment epithelial (RPE) cells (Vmd2-Bmp4 Tg mice), and used the laser-induced choroidal neovascularization (CNV) model to study the angiogenic properties of BMP4 in adult
eyes. Vmd2-Bmp4 Tg mice displayed normal retinal histology at 10 weeks of age when compared with age-matched wildtype mice. Over-expression
of BMP4 in RPE in the transgenic mice was confirmed by real-time PCR and immunostaining. Elevated levels of Smad1,5 phosphorylation
were found in BMP4 transgenic mice compared to wildype mice. Over-expression of BMP4 was associated with less severe CNV as
characterized by fluorescein angiography, CNV volume measurement and histology. While control mice showed increased levels
of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9 after laser injury, Vmd2-Bmp4 Tg showed no increase in either VEGF or MMP-9. Further, we found that TNF-induced MMP-9 secretion in vitro was reduced by
pretreatment of RPE cells with BMP4. The inhibition of MMP-9 was Smad-dependent because BMP4 failed to repress TNF-induced
MMP-9 expression when Smad1,5 was silenced by siRNA. In summary, our studies identified an anti-angiogenic role for BMP4 in
laser-induced CNV, mediated by direct inhibition of MMP-9 and indirect inhibition of VEGF. |
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