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Over-expression of BMP4 inhibits experimental choroidal neovascularization by modulating VEGF and MMP-9

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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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Authors and Affiliations

  1. Department of Ophthalmology, Keck School of Medicine, The University of Southern California, Los Angeles, CA, USA

    Jing Xu, Shozo Sonoda, Shikun He, Christine Spee, Stephen J. Ryan & David R. Hinton

  2. The Doheny Eye Institute, Los Angeles, CA, USA

    Jing Xu, Danhong Zhu, Shozo Sonoda, Shikun He, Christine Spee, Stephen J. Ryan & David R. Hinton

  3. Department of Pathology, Keck School of Medicine, The University of Southern California, 2011 Zonal Ave., HMR 209, Los Angeles, CA, 90089, USA

    Danhong Zhu, Shikun He & David R. Hinton

  4. Department of Ophthalmology, Kagoshima University, Kagoshima, Japan

    Shozo Sonoda

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  1. Jing Xu
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  2. Danhong Zhu
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  3. Shozo Sonoda
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  4. Shikun He
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  5. Christine Spee
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  7. David R. Hinton
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Correspondence to David R. Hinton.

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Jing Xu and Danhong Zhu contributed equally.

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Xu, J., Zhu, D., Sonoda, S. et al. Over-expression of BMP4 inhibits experimental choroidal neovascularization by modulating VEGF and MMP-9. Angiogenesis 15, 213–227 (2012). https://doi.org/10.1007/s10456-012-9254-4

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  • DOI: https://doi.org/10.1007/s10456-012-9254-4

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