TUESDAY, Oct. 9, 2001 (HealthDayNews) -- Low oxygen levels in the body's tissues may be what sparks a protein to create new blood vessels when needed, such as for tough-to-heal wounds, suggests a new study in mice.
And making healthy blood vessels grow could help patients with diabetes or cardiac and peripheral vascular disease, say researchers at the University of California in San Francisco (UCSF).
While previous studies focused on a molecule called vascular endothelial growth factor (VEGF), which is vital in creating vessels, the UCSF researchers tried to kick start vessel growth using a protein called hypoxia-inducible factor-1 alpha (HIF-1a) that responds to low oxygen (hypoxic) conditions.
"It's called a master regulatory gene," says senior investigator Dr. Jeffrey Arbeit, associate professor of surgery. HIF-1a is at the top of a hierarchy of genetic switches, turning on more than one gene, including those involved with tissue and vessel growth, he says. (HIF-1a is a small protein subunit of the larger HIF-1 protein, which in turn is part of HIF, a gene-stimulating factor.)
Arbeit and his colleagues engineered a strain of mice to show the effects of the human HIF-1a gene in the animals' skin cells. "The principal target of this molecule is vascular endothelial growth factor [VEGF]," says Arbeit.
They found that the continuous activation of the HIF-1a gene produced a 13-fold increase in the effects of VEGF and a 66 percent increase in skin capillaries. In fact, the effect was so intense that the formation of new skin capillaries in the mice was visible to the naked eye, Arbeit says.
The findings appear in this month's issue of Genes & Development.
Dr. Hugo Marti, a member of the Hypoxia-Induced Gene Expression Laboratory at the University of Zurich in Zurich, Switzerland, says HIF-1a is the most important factor involved in how organisms adapt to limited oxygen conditions.
"If you have hypoxia somewhere in the organism, HIF is activated, and then it binds to all these sequences in the genes, which are regulated by HIF. One of these is VEGF."
Hypoxia starts a chemical cascade, he says."Hypoxia is the trigger, [followed by] the activation of HIF, which then, in turn, increases expression of VEGF." The HIF locks into the VEGF in endothelial cells that line the organs of the body. Those cells then start to divide and to sprout to form new blood vessels from existing capillaries. "This is what we call angiogenesis."
Under ideal conditions the system manages itself, says Marti. "If you produce more vessels, then you get more oxygen to the tissues, and then HIF-1 gets switched off. If HIF-1 is switched off, then VEGF expression is down, and then angiogenesis stops."
Previous studies have attempted to trigger vessel growth by creating too much VEGF, but that produces a problem with the blood vessels. "They're leaky," says Arbeit. "Even in clinical trials [that give] VEGF as gene therapy, patients get limb edema [swelling]."
Arbeit says why the blood vessels that form as a result of HIF-1a are closer to normal blood is not clear.
Marti speculates that stimulating vessel growth from the HIF-1a stage may stimulate other factors that may block VEGF-induced leakage.
Arbeit says that the study's results also could be used to find ways to prevent blood vessel growth to cancerous tumors. Lack of oxygen also may trigger the cutoff of supply lines to harmful tissue growth, including cancer, he says.
At the same time, he says patients with peripheral vascular disease and diabetes, which involve low-oxygen conditions in tissues, could benefit from new vessel growth.
However, Arbeit says mice used in his study express HIF-1a constantly, and that future studies will need to look at the effect of the protein in animals whose physiologic systems are more like humans. He says trials of HIF-1a in humans could be only a couple of years away.