Americans die of heart or
cardiovascular disease at an alarming rate. In fact, heart attacks, strokes and
related diseases will kill an estimated 610,000 Americans this year alone. Some
medications help, but to better tackle this problem, researchers need to know
exactly how the heart and blood vessels stay healthy in the first place.
Now,
scientists at The Scripps Research Institute have identified a protein, called
GPR68, that senses blood flow and tells small blood vessels called arterioles
when to dilate. The researchers believe medications that activate GPR68 could
one day be useful to treat medical conditions, including ischemic stroke.
"It
has been known for decades that blood vessels sense changes in blood flow rate,
and this information is crucial in regulating blood vessel dilation and
controlling vascular tone," says Ardem Patapoutian, PhD, Scripps Research
professor, Howard Hughes Medical Institute investigator and senior author of
the study published today in the journal Cell.
Indeed,
flow-mediated dilation (FMD) is a non-invasive clinical test that informs
doctors about the health of the vascular system. A compromised FMD is a precursor
to a wide array of vascular diseases such as hypertension and atherosclerosis.
"Despite
the importance of this process, the molecules involved within arteries to sense
blood flow have remained unknown," Patapoutian says.
Patapoutian
and first author Jie Xu, PhD, a postdoctoral fellow in the lab, and now an
independent scientist at the Genomics Institute of the Novartis Research
Foundation (GNF), led the project to find GPR68 and determine how it works. The
team started by designing a machine that uses turbulent movement of liquid to
stand in for blood flow in blood vessels. This machine uses 384 pistons that
move the fluid up and down over a bed of cells, placed in 384 wells on a plate.
This motion simulates how blood would put pressure on those cells.
The
researchers put this machine to work testing a series of cell lines, some of
which had mutations that led to an overexpression of proteins potentially
linked to pressure sensing. The researchers then performed a screen, knocking
down the expression of different candidate genes in each of the 384 wells, and
tested if that gene is required for responding to the machine's turbulent
pressure.
The
tests pointed the researchers to GPR68, which the authors showed works as a
sensor of mechanical stimulation. Further experiments suggested that GPR68 is
essential for FMD. "In a model organism, this protein is essential for
sensing blood flow, and the proper functioning of the vascular system,"
says Patapoutian.
When
arterioles can't dilate properly, the body has fewer options for lowering blood
pressure in people with hypertension or getting blood through clogged vessels
in cases of atherosclerosis.
"Future
work will explore the role of GPR68 in clinically relevant cardiovascular
diseases," Patapoutian says. "We are also exploring the possibility
of using small molecules to modulate the function of GPR68, as such molecules
could be beneficial in the clinic."
