How blood flow dictates gene expression

December 20, 2006

(PHILADELPHIA) -- Researchers at the University of Pennsylvania School of Medicine have pinpointed a key regulatory protein that translates blood flow into gene expression. The investigators showed that in a model of mouse embryonic development a transcription factor called Klf2, which resides in cells that line blood vessels, is activated by rapid, pulsed blood flow, as reported in the December issue of Developmental Cell. Understanding Klf2's role in blood vessel and muscle biology could help with fighting atherosclerosis.

"We always knew that there had to be this line of communication from the vessel lining, or endothelium, to the smooth muscles, which never sees a blood cell," says senior author Mark Kahn, MD, Associate Professor of Medicine. "That's where Klf2 fits: This is the first time, at a molecular level, that this chain has been demonstrated in an animal."

Swirling eddies of blood form when vessels branch, much like when a river divides. Atherosclerosis typically forms at these sites of so-called disturbed flow as opposed to regions of rapid blood flow through the main vessels. This relationship between atherosclerosis and flow has been known for decades. More recently, tissue- culture studies have shown that Klf2 is activated by increased blood flow, or "fluid sheer stress."

Indeed, in this study Kahn; first author John S. Lee, MD, PhD, Instructor in the Department of Medicine; and colleagues show that the expression of Klf2 in a developing mouse embryo mirrors events in previous tissue-culture studies. They found that Klf2 is expressed on the high-flow side of developing mitral and aortic valves in the heart of a 14-day-old embryo.

The researchers surmise that the mechanical stimulus of blood flowing in a vessel leads to the upregulation of Klf2, which either activates or represses genes that control smooth muscle tone, that is the caliber of the vessel. (Tone is governed by how much a muscle contracts or relaxes.) These genes encode proteins that are either secreted or are on the cell surface of the endothelium and so influence how smooth-muscle cells contract or relax.

The researchers suggest that when Klf2 is expressed, smooth muscle cells lining the blood vessels maintain their ability to regulate vessel tone. However, when Klf2 is genetically deleted, or "knocked out," from the blood vessels of mouse embryos, they had an abnormally high cardiac output, as measured by ultrasound, while the overall structure of their blood vessels was normal. These findings implicate loss of vessel tone as the primary defect in Klf2 knockout mice.

Now that Klf2 has been established as an important regulator of blood flow in live animals and is required for the development of a healthy cardiovascular system, the next step is to elucidate the role of Klf2 in normal adult blood vessels and in the pathogenesis of vascular diseases, such as atherosclerosis.
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Co-authors are Eric Sebzda, Cara Bertozzi, Mei Chen, Patti Mericko, Diane Zhou, Lan Chen, and John J. Lepore from Penn; Qing Yu and Cecelia W. Lo from the National Heart, Lung and Blood Institute; Jordan T. Shin and Calum A. MacRae from Massachusetts General Hospital, Charlestown, Mass., and Matthias Stadtfeld and Thomas Graf from Albert Einstein College of Medicine, New York. This research was funded by the National Heart, Lung and Blood Institute.

This release and related images can be viewed at www.pennhealth.com/news.

PENN Medicine is a $2.9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three hospitals, all of which have received numerous national patient-care honors [Hospital of the University of Pennsylvania; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

University of Pennsylvania School of Medicine

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