|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Blood, 1 July 2004, Vol. 104, No. 1, pp. 6-7.
VEGF up-regulates DSCR1: more surprisesHARVARD MEDICAL SCHOOL
Vascular endothelial growth factor (VEGF) unexpectedly induces the expression of the Down syndrome critical region protein-1 (DSCR1), an inhibitor of the calcineurin signaling pathway, in endothelial cells, leading to down-regulation of several inflammatory genes after initial stimulation.
Using a gene expression profiling approach, Hesser et al observed that DSCR1 was the most highly up-regulated gene in several types of human endothelial cells after VEGF treatment. DSCR1 is one of many gene products that have been associated with Down syndrome and belongs to a family of proteins that interact with the phosphatase calcineurin A (CnA). The authors showed that in human endothelial cells DSCR1 repressed several inflammatory genes by inhibiting nuclear translocation of nuclear factor of activated T cells (NFAT)—a transcription factor that is regulated by CnA. Previous studies had shown the ability of DSCR1 to inhibit CnA in other cell types, and Hesser et al observed that this was also the case in endothelial cells. So it appears that VEGF up-regulation of DSCR1 leads to the inhibition of CnA, and therefore prevents the translocation of NFAT to the nucleus and the transcription of proinflammatory genes. These genes include COX2, E-selectin, and tissue factor; so modulation of DSCR1 might represent a novel therapeutic approach to control inflammation at the level of the vasculature. CnA is also the target of the potent immunosuppressive drug cyclosporine A (CsA), which is widely used to inhibit transplant rejection. CsA blocks CnA signaling, however, by a different mechanism than DSCR1, and in vitro studies indicate that CsA inhibits lymphocyte functions at low concentrations that do not affect endothelial cell signaling. The long-term therapeutic use of CsA has been associated with a number of adverse effects that include nephrotoxicity, renal vascular damage, and hypertension.1 The sites of major vascular damage by CsA overlap with the sites of physiologic expression of VEGF and VEGF receptors in healthy adults. It will therefore be of interest to determine whether physiologic levels of VEGF expression in adult renal tissues are sufficient to induce DSCR1 expression. If so, a synergistic inhibition of CnA signaling by DSCR1 combined with CsA might contribute to chronic CsA-induced renal toxicity. VEGF inhibitors are being developed and have been tested in the clinic as antiangiogenic therapies for cancer and other diseases. The discovery of DSCR1 as a major target of VEGF signaling in endothelial cells therefore raises important questions regarding the biologic consequences of long-term inhibition of VEGF signaling. Does blockade of VEGF signaling result in impaired expression of DSCR1 in the tumor endothelium or in normal vasculature? If so, the decreased activity of DSCR1 might contribute to the frequently observed increase in E-selectin and tissue factor levels in patients treated with VEGF signaling inhibitors,2 which cause vascular injury and other effects. This pathway could also underlie other side effects, such as the increased thrombosis or proteinuria that have been observed in clinical trials with inhibitors of VEGF bioactivity.3 Administration of compounds that mimic the biologic activity of DSCR1, such as CsA, might compensate for the potential decrease in DSCR1 expression in patients who undergo chronic anti-VEGF therapy. Finally, the findings of Hesser et al raise the question of whether the increase in DSCR1 expression observed in individuals with Down syndrome or Alzheimer disease4 might affect CnA activity in their endothelial cells, and whether such a potential vascular perturbation might contribute to disease pathogenesis. If so, VEGF signaling would be involved in an unexpected new realm of disease mechanisms. References
  CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Article in Blood Online:
This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2004 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
