For Release: 5 pm ET, November 1, 2007
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Super Heart Mice Reveal Blood Vessel Growth Controls Organ Size

Dr. Michael Simons
Dr. Michael Simons

HANOVER, NH—Dartmouth Medical School researchers have created mice with super hearts—enlarged organs that are powerful blood pumps—demonstrating a new dynamic for regulating heart size and function. The work, reported in the November issue of the Journal of Clinical Investigation, offers novel approaches for heart disease therapies. Moreover, it opens a window on what drives organ enlargement and how to control organ size in adults.

Mice are small, people are big; what determines their size is a fundamental issue, according to Dr. Michael Simons, professor of medicine and of pharmacology and toxicology at DMS and chief of cardiology at Dartmouth-Hitchcock Medical Center, who led the research team.

"No matter their size, at the tissue level, a human and mouse have the same cell size. Likewise, they have same number of blood vessels per gram of tissue—any tissue. What's different for each is the number of cells and what determines that number."

Simons and his colleagues wondered what would happen if they increased the network of blood vessels—the vasculature—in an adult organ. They genetically engineered adult mice with hearts that grew new blood vessels, a process called angiogenesis. And they found that vessel density controls organ size.

The investigators turned on a gene that expresses an angiogenic growth factor called PR39. In three weeks normal mice hearts made many new vessels, increasing their vasculature mass by about 50 percent, and by six weeks their hearts became enlarged by about 50 percent.

In practical terms, then, we can potentially enhance the size of functionally damaged organs like the heart.

—Dr. Michael Simons

The number of heart cells didn't increase, but the size of the cells the heart made became bigger. The increase stopped when the ratio of blood vessels to gram per tissue returned to its normal value. Further analysis indicated nitric oxide drives the process.

When the researchers turned off the growth factor the mouse heart remained enlarged and functioned much better. "It became a super heart, pumping like mad. The mouse is not making new tissue, but making existing tissue bigger, which controls function in most cases, " Simons said.

Normally a pathological stimulus, such as increased blood pressure, obstructed valve or vessel narrowing prods the heart to compensate by increasing the size of its muscle cells (known as cardiac hypertrophy). The vasculature also expands, but often fails to keep up with increase of the heart itself, so the enlarged organ fails.

"We did it other way around; there was no stimulus for the heart to get bigger, only increased vasculature. It's probably a different type of hypertrophy, because the heart actually remained functional and very strong." Simons said.

Mice that had a heart attack also benefited from induced angiogenesis, the researchers demonstrated. Though not fully recovered, they had bigger and better hearts than non stimulated ill counterparts. "In practical terms, then, we can potentially enhance the size of functionally damaged organs like the heart, " Simons said.

Further afield, he speculated on performance boosting opportunities for athletes. It might be possible to express angiogenic growth factor in skeletal muscle to grow bigger muscles without detection.

Co-authors are DMS colleagues Daniela Tirziu, Karen L. Moodie, Robert T. Palac, Zhen W. Zhuang, Qiangwei Fu, Arye Elfenbein and Amy E. Hall, as well as collaborators from Katholieke Universiteit Leuven, Leuven, Belgium. And Ludwig Institute for Cancer Research, , Stockholm, Sweden.


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