Bruce Spiegelman, PhD
Researchers at Dana-Farber Cancer Institute have found a previously
unknown molecular pathway in mice that spurs the growth of new blood
vessels when body parts are jeopardized by poor circulation.
At present, their observation adds to the understanding of blood
vessel formation. In the future, though, the researchers suggest it is
possible that the pathway could be manipulated as a means of treating
heart and blood vessel diseases and cancer. The paper appears in the
Feb. 21 issue of the journal Nature.
Bruce Spiegelman, PhD, and his colleagues at Dana-Farber discovered
that PGC-1alpha — a key metabolic regulatory molecule — senses a
dangerously low level of oxygen and nutrients when circulation is cut
off and then triggers the formation of new blood vessels to re-supply
the oxygen-starved area — a process known as angiogenesis.
A similar response to hypoxia, or oxygen deprivation, has been
observed before. The response is regulated by a group of proteins known
as Hypoxia Inducible Factors (HIF) that detect hypoxia and activate the
production of VEGF (vascular endothelial growth factor). VEGF, in turn,
The newly discovered pathway provides "an independent way of getting
there," says Spiegelman, who is also a professor of cell biology at
Harvard Medical School. Along with lead author Zoltan Arany, MD, PhD,
and colleagues, Spiegelman found that HIF was completely left out of the
loop when PGC-1alpha accomplished the same feat in single cells and in
live mice using a different regulator, known as ERR-alpha
When the scientists knocked out the activity of PGC-1 alpha (which
was first identified in the Spiegelman lab) in cells and live mice, the
hypoxia-induced response and angiogenesis were sharply decreased.
"We were surprised to find this novel mechanism," comments Spiegelman.
"It was apparently there all along," adds Arany. "That means there is
now a second pathway that you need to know about if you are trying to
activate or inhibit angiogenesis."
Angiogenesis occurs in the normal development of the body, but it's
also an on-call service when an injury or an artery blockage — the cause
of heart attacks and strokes leaves normal tissues starved for blood.
Generating a new network of small vessels to nourish the area can
protect against further injury. Muscle-building exercise also triggers
angiogenesis to provide circulation for the enlarging muscle tissue.
On the downside, cancer has evolved the ability to commandeer VEGF
and other angiogenic factors to encourage blood vessel growth around
tumors that have outgrown their oxygen supplies.
In recent years, companies have developed a number of drugs that
manipulate the angiogenic pathway — in both directions. Among them are
anti-angiogenic cancer drugs, including thalidomide and Avastin, which
are designed to starve tumors by blocking the formation of blood
vessels. Avastin is also used to dampen the abnormal growth of small
vessels in the retina that causes macular degeneration in the eye.
Conversely, researchers have tried using VEGF and other compounds to
improve the circulation in the legs and feet — and even heart muscle —
of patients with poor blood supply.
"We're still far from having good drugs to modulate angiogenesis
through the HIF pathway," commented Arany. The discovery of a second,
alternate pathway, involving PGC-1 alpha and ERR-alpha, leading to
angiogenesis may offer new opportunities for therapy "in any situation
where angiogenesis is a factor," he said.
Co-authors of the paper are Shin-Yin Foo, MD, PhD, and Anthony
Rosenzweig, MD, of Beth Israel Deaconess Medical Center and the Harvard
Stem Cell Institute; Yanhong Ma, PhD, Jorge Ruas, PhD, Archana
Bommi-Reddy, PhD, Geoffrey Girnun, PhD, Marcus Cooper, MD, and Dina
Laznik of Dana-Farber; Kwan Hyuck Baek, PhD, of Children's Hospital
Boston; and Shamina Rangwala, PhD, of the Novartis Institute.
The research was supported by grants from the National Institutes of
Health and the Wenner-Gren Foundation and Leducq Foundation.
Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National