UT Southwestern Researchers Identify Gene As Essential For Vascular Smooth Muscle Development

Their work appears in today's issue of Nature.

Smooth muscle cells are essential for the formation and function of the cardiovascular system, as well as many internal organs such as the stomach, intestine, bladder and uterus. Abnormalities in their growth can cause a wide range of human disorders, including atherosclerosis, hypertension, asthma and leiomyosarcoma (a fatal smooth-muscle cancer). The molecular mechanisms that control smooth muscle cell growth and differentiation, however, have been poorly understood.

"It has long been known that many diseases result from abnormal growth of smooth muscle cells," said Dr. Eric Olson, chairman of molecular biology and senior author of the study. "The new findings are quite exciting because they reveal a previously unknown mechanism that controls the growth and differentiation of smooth muscle cells. Knowing this mechanism, we can think about ways of regulating it to control smooth muscle growth during disease."

Dr. Olson recently discovered a master regulator of smooth muscle development, a protein called myocardin. This regulator turns on smooth muscle genes by interacting with serum response factor (SRF), a widely expressed protein that binds DNA.

In the Nature study, Dr. Olson and his colleagues showed that the ability of myocardin to turn on smooth muscle genes is counteracted by another protein, Elk-1, which prevents myocardin from binding to SRF. When Elk-1 displaces the myocardin from SRF, it triggers smooth muscle cell proliferation, an effect associated with cardiovascular disease.

With these findings, scientists now have important new insights into the cellular mechanisms that control the growth and differentiation of smooth muscle cells. The findings also offer many interesting opportunities for therapeutic intervention, said Dr. Olson, director of the Nancy B. and Jake L. Hamon Center for Basic Research in Cancer and the Nearburg Family Center for Basic Research in Pediatric Oncology.

Other UT Southwestern contributors to the Nature study were Zhigao Wang, student research assistant in molecular biology, and John McAnally, research associate in molecular biology. Researchers from the University of North Carolina, Chapel Hill, and Tuebingen University in Germany also contributed.

The research was supported by grants from the National Institutes of Health, the McGowan Foundation, the Donald W. Reynolds Foundation, the Robert A. Welch Foundation, the Muscular Dystrophy Association and the German research foundation Deutsche Forschungsgemeinschaft.