(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
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.”
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
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
proteins that are either secreted or are on the cell surface of
the endothelium and so influence how smooth-muscle cells contract
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
diseases, such as atherosclerosis.
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.
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