Sonic hedgehog may help overcome problems associated with FGF2 and VEGF therapy

Jun 18 2006

The newest concept for treating coronary artery disease is to induce hearts to grow their own new blood vessels to bypass damaged tissue or clogged arteries.

Unfortunately, clinical trials of two important blood-vessel growth factors -- fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor (VEGF) -- have not produced stellar results.

Now researchers at Washington University School of Medicine in St. Louis have investigated a third signaling molecule -- called Sonic hedgehog -- that could overcome problems associated with FGF2 and VEGF therapy.

In a report appearing in Genes and Development, the team showed that activating hedgehog signals in adult mouse hearts led to an increase in the density of blood vessels in the heart.

Their findings suggest that a drug treatment that turned on or increased hedgehog signals could provide substantial benefit to patients suffering from ischemic heart disease and myocardial infarctions and offer an alternative to invasive procedures like surgery or angioplasty.

About 12 percent of heart patients are not eligible for bypass surgery, which redirects blood around clogged arteries, or for other procedures routinely used to open clogged vessels. That means each year in the United States, 100,000 to 200,000 patients could benefit from having another option for improving blood flow in the heart, according to the study's authors.

"Our study is the first to identify that hedgehog signaling pathways are operational in the developing and mature heart," says senior author David Ornitz, M.D., Ph.D., the Alumni Endowed Professor of Molecular Biology and Pharmacology.

The hedgehog gene was discovered in fruit flies and named for the spiky appearance of fruit fly embryos with mutations of the gene.

"Hedgehog signaling is a good potential target for growing new vessels in the heart," says first author Kory Lavine, graduate student in molecular biology and pharmacology and student in the Medical Scientist Training Program. "The new vessels would provide an alternative route of blood flow, bypassing clogged vessels and other damage. In effect, hedgehog treatment could grow a natural bypass."

In three large clinical studies, the blood-vessel growth factors FGF2 and VEGF did not result in significant improvement in heart patients who received them.

The Washington University scientists demonstrated that hedgehog has an advantage over these growth factors for possible treatment of heart disease because it specifically stimulates blood vessel formation and does so by orchestrating the expression of multiple other growth factors that work together to build new vessels.

"Research on development in embryonic mouse hearts has shown that the heart needs multiple factors expressed at the right time, in the right amounts and in the right pattern to grow blood vessels that function properly," Lavine says. "The best way to achieve that is to use a factor that controls and coordinates the activity of multiple blood-vessel growth factors, and we've found that hedgehog has this ability."

The researchers showed that hedgehog controlled four growth factors: three VEGF proteins (termed VEGF A, B and C) and a protein called angiopoietin 2. They found that hedgehog is sufficient to stimulate normal development of blood vessels in embryonic mouse hearts -- under hedgehog's control, the blood vessels spread out in an orderly fashion from the top of the ventricles of the growing heart to the bottom.

The researchers are continuing their studies of hedgehog signaling in the heart to determine its utility in treating heart disease.