Pumping new life into an old problem

TSRI researchers find that a molecule that dilates blood vessels may herald a new way to treat heart disease

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LA JOLLA, Calif.—One of the challenges in pharma in biotech is the frequency of instances in which we may have therapeutics that work against a particular ailment, but we don’t always know all that we should about the etiology of that ailment. As such, cures may work, but we don’t always know precisely why, and we may miss out on discovering and developing better and more targeted interventions.
And so it is with the cardiovascular system: We know a lot about it, but there’s still much we don’t know about precisely how the heart and blood vessels stay healthy in the first place. Researchers at The Scripps Research Institute (TSRI) are setting about trying to fill that knowledge gap, in that they 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,” said Dr. Ardem Patapoutian, a TSRI professor, Howard Hughes Medical Institute investigator and senior author of the study published recently in the journal Cell under the title “GPR68 Senses Flow and is Essential for Vascular Physiology.”
The knowledge that Patapoutian refers to is why there is a non-invasive clinical test called flow-mediated dilation (FMD) that helps physicians and others assess the health of the vascular system; a compromised FMD is a precursor to hypertension and atherosclerosis and other vascular diseases. And yet, “Despite the importance of this process, the molecules involved within arteries to sense blood flow have remained unknown,” Patapoutian noted.
Patapoutian and first author Dr. Jie Xu, 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. 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 and testing in each case if the 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,” explained 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.”
The study also included authors from GNF; the MITOVASC Institute; the Indiana University School of Medicine; and the University of California, San Diego.
In other recent cardiovascular news from TSRI, Dr. Velia Fowler, and her lab reported that a protein called myosin IIA contracts to give red blood cells their distinctive shape. The findings, published in the journal Proceedings of the National Academy of Sciences under the title “Myosin IIA interacts with the spectrin-actin membrane skeleton to control red blood cell membrane curvature and deformability,” could shed light on sickle cell diseases and other disorders where red blood cells are deformed.
“Red blood cells have been studied for centuries, but there are still a lot of unanswered questions about how they adopt their shape,” said Alyson Smith, a graduate student at TSRI and co-first author of the study. “Our study adds an important piece to this puzzle.”
Fowler says, for example, that there might be a chance someday to inhibit myosin IIA in red blood cells and restore some of elasticity they lose in sickle cell anemia, letting them bend and fit through capillaries.
“Even just a small change in those sickle cells might be enough,” says Nowak, who served as study co-first author with Smith.
This view of red blood cell shape has sparked many new questions. The study suggests that cells use a process called phosphorylation to make the myosin IIA filaments on the cell membrane more stable—but how this process is controlled remains a mystery. Going forward, the researchers hope to learn more about what regulates myosin IIA’s activity in red blood cells and even other cell types, like neurons.

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