Down‐regulation of Flt‐1 gene expression by the proteasome inhibitor MG262

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Abstract
The mechanisms involved in the anti‐angiogenic actions of the proteasome inhibitors are poorly understood. Here, we report that the gene expression of the VEGF receptor Flt‐1 (vascular endothelial growth factor receptor 1) was down‐regulated by the reversible proteasome inhibitor MG262 in explant cultures of the developing chicken pecten oculi, a vascular organ consisting of endothelial cells, pericytes, and macrophages. In addition, the inhibitor prevented the induction of Flt‐1 by lipopolysaccharide (LPS) in macrophages and down‐regulated the expression of Flt‐1 after LPS induction. Flt‐1 gene expression was also down regulated by MG262 in cultures of human microvascular endothelial cells. Interestingly, a transcript of Flt‐1, coding for a soluble form of the receptor (sFlt‐1) with anti‐angiogenic properties, was not down‐regulated in the same extent. Only a small decrease in the expression of VEGF and Ang‐2 was detected in the pecten oculi upon inhibition of the proteasome, while no major changes were observed in the expression of other angiogenic molecules, such as KDR or Ang‐1. Since recent experiments have demonstrated the importance of anti‐Flt‐1 therapy in the inhibition of tumor angiogenesis, retinal angiogenesis, arthritis, and atherosclerosis (Luttun et al. [2002]: Nat Med 8:831–840), our observation on down‐regulation of Flt‐1 in microvascular endothelial cells and macrophages by MG262 supports the postulated role of the proteasome inhibitors as potential candidates for therapeutic modulation of angiogenesis and inflammation.