VEGF-B inhibits apoptosis via VEGFR-1–mediated suppression of the expression of BH3-only protein genes in mice and rats
Yang Li, … , Carl-Henrik Heldin, Xuri Li
Yang Li, … , Carl-Henrik Heldin, Xuri Li
Published February 7, 2008
Citation Information: J Clin Invest. 2008;118(3):913-923. https://doi.org/10.1172/JCI33673.
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Research Article Angiogenesis

VEGF-B inhibits apoptosis via VEGFR-1–mediated suppression of the expression of BH3-only protein genes in mice and rats

Abstract

Despite its early discovery and high sequence homology to the other VEGF family members, the biological functions of VEGF-B remain poorly understood. We revealed here a novel function for VEGF-B as a potent inhibitor of apoptosis. Using gene expression profiling of mouse primary aortic smooth muscle cells, and confirming the results by real-time PCR using mouse and rat cell lines, we showed that VEGF-B inhibited the expression of genes encoding the proapoptotic BH3-only proteins and other apoptosis- and cell death–related proteins, including p53 and members of the caspase family, via activation of VEGFR-1. Consistent with this, VEGF-B treatment rescued neurons from apoptosis in the retina and brain in mouse models of ocular neurodegenerative disorders and stroke, respectively. Interestingly, VEGF-B treatment at the dose effective for neuronal survival did not cause retinal neovascularization, suggesting that VEGF-B is the first member of the VEGF family that has a potent antiapoptotic effect while lacking a general angiogenic activity. These findings indicate that VEGF-B may potentially offer a new therapeutic option for the treatment of neurodegenerative diseases.

Authors

Yang Li, Fan Zhang, Nobuo Nagai, Zhongshu Tang, Shuihua Zhang, Pierre Scotney, Johan Lennartsson, Chaoyong Zhu, Yi Qu, Changge Fang, Jianyuan Hua, Osamu Matsuo, Guo-Hua Fong, Hao Ding, Yihai Cao, Kevin G. Becker, Andrew Nash, Carl-Henrik Heldin, Xuri Li

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Figure 3

VEGF-B inhibits axotomy-induced apoptosis in the retina.

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VEGF-B inhibits axotomy-induced apoptosis in the retina. (A) VEGF-B is h...
(A) VEGF-B is highly expressed in the retina as shown by the in situ hybridization assay. A high level of VEGF-B expression was found primarily in the RGCs and the inner and outer nuclear layers (INL and ONL, arrows). VEGFR-1 expression was mainly found in the inner plexiform layer, part of the inner nuclear layer, and the inner and outer segment layers (IS, OS). Scale bar: 50 μm. (B and C) Real-time PCR assay showed that VEGF-B (B) and VEGFR-1 (C) expression were upregulated in the retinae after ONC injury. The upregulation was seen as early as 6 hours after ONC and reached a high level after 1 week. (D–F) A single dose of VEGF-B167 intravitreal treatment increased the number of viable RGCs by about 1.7-fold. VEGF-B neutralizing antibody intravitreal treatment decreased the number of viable RGCs by about 33% (F). VEGFR-1 ECD treatment decreased the number of viable RGCs by about 42% (F). Scale bar: 10 μm. (G–J) Real-time PCR analysis revealed that VEGF-B167 treatment inhibited the expression of the BH3-only protein genes Noxa (G) and Bmf (H), as well as Bak (I) and p53 (J) expression in both normal and ONC-injured retinae. *P < 0.05, **P < 0.01.