|
Many vascular disorders including atherosclerosis,
tumor growth, and inflammation are caused by the activation and
dysfunction of the endothelium. This layer of cells lines the inside
of blood vessels and regulates many processes including new blood
vessel formation, blood vessel diameter, blood clotting, the migration
of circulating white blood cells, and the normal release of molecules
involved in inflammation
"Because endothelial cells are so active, any
perturbation in their function may have undesirable effects," explains
Dr. Takashi Minami of the University of Tokyo. "Indeed, endothelial
cell dysfunction underlies many disease states in humans,
including--but certainly not limited to--stroke, coronary artery
disease, cancer and preeclampsia. An important goal in vascular
research is to develop new strategies that inhibit endothelial cell
dysfunction and abnormal blood vessel formation."
Certain agonists, such as vascular endothelial
growth factor and the serine protease thrombin, cause endothelial
cells to increase their expression of genes involved in proliferation,
inflammation, and thrombosis. Dr. Minami and his colleagues found that
these agonists also turn on a gene that produces Down Syndrome
Critical Region 1 (DSCR-1), and that DSCR-1 then negatively feeds back
on the agonists and shuts off their production. Thus, DSCR-1 acts as a
circuit breaker in agonist signaling, and serves in a negative
feedback loop to inhibit endothelial cell activation and growth.
More importantly, Dr. Minami and his colleagues
discovered that when DSCR-1 is overexpressed in mice, it blocks the
formation of new blood vessels and thereby reduces tumor growth.
"It has long been recognized that patients with
Down syndrome have reduced risk for developing solid tumors and
atherosclerosis," notes Dr. Minami. "DSCR-1 may be expressed at higher
levels in patients with Down syndrome. Based on the results of the
current study, it is interesting to speculate that the DSCR-1
auto-inhibitory loop in endothelial cells is responsible--at least in
part--for the reduced risk for tumors and atherosclerosis in this
patient population."
This connection between overexpression of DSCR-1
and a reduced risk for solid tumors and inflammatory states such as
atherosclerosis may eventually be used for therapeutic gain in
non-Down syndrome patients. "The development of methods to overexpress
DSCR-1 in the endothelium would provide a novel strategy for reducing
blood vessel formation and thus tumor growth, and for dampening
endothelial cell dysfunction," says Dr. Minami. |
