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

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Sonic hedgehog may help overcome problems associated with FGF2 and

VEGF therapy

http://www.news-medical.net/?id=18486

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 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.

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