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P. Arjunan, Y. Li, F. Zhang, Z. Tang, C.-H. Heldin, X. Li; VEGF-B Inhibits the Expression of Apoptotic/Cell Death-Related Genes in Multiple Types of Cells. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4948.
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To determine the anti-apoptotic effect of VEGF-B, we performed the genome-wide gene expression profiling and identified the VEGF-B regulated genes.
The mouse primary aortic smooth muscles cells expressing VEGFR-1 were treated with human recombinant VEGF-B167 protein under hypoxia (1% oxygen), a condition in which VEGFR-1 is up-regulated in these cells. Results revealed that VEGF-B treatment significantly down-regulated the expression of about six hundred genes by more than two-fold. Among the significant genes consisted in the apoptosis/cell death-related pathways, those ranked among the top 3 in terms of significance in down-regulation - Bmf (~10-fold), TrP53inp1 (~ 8-fold), and DCN (~ 7-fold)- were found to be critically involved in apoptosis.
For verification of the microarray data, five different cell lines - RGC5 (rat retinal ganglion cell-derived), TR-rPCT (immortalized rat retinal pericyte), TR-MUL (immortalized rat retinal, Müller), TR-iBRB (immortalized rat retinal endothelial), and the mouse primary aortic smooth muscle cells (mSMC) - were treated with VEGF-B167 (100 ng/ml) for six hours in either normoxic or hypoxic (1% oxygen) conditions, and the expression of the apoptotic/cell death-related genes investigated by real-time PCR. Consistent with the microarray data, the expression of many apoptotic/cell death-related genes were found to be significantly inhibited by VEGF-B. Among them, the expression of most of the BH3-only protein genes (Bmf, Hrk, Puma, Noxa (Pmaip1), Bid, Bad, Bik) was inhibited by VEGF-B in all types of cells examined. The BH3-only protein genes are therefore the major target genes suppressed by VEGF-B. It also inhibited the expression of p53, the caspases (Casp2, Casp8, Casp9, Casp12), and other apoptotic/cell death-related genes (Bak, Bax, Bcl2l11, TNF-α, Dcn, Olr1, etc).
In conclusion, the VEGF-B inhibited the expression of the BH3-only protein and other apoptotic/cell death-related genes, indicating a general anti-apoptotic effect of VEGF-B in different cell types, and thus may provide a new therapeutic intervention for retinal degenerative process.
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